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  • 1.
    Albrecht, Inka
    et al.
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Wick, Cecilia
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Hallgren, Asa
    Karolinska Inst, Dept Med Solna, Expt Endocrinol, SE-17176 Stockholm, Sweden..
    Tjarnlund, Anna
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Nagaraju, Kanneboyina
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Andrade, Felipe
    Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA..
    Thompson, Kathryn
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Coley, William
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Phadke, Aditi
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Diaz-Gallo, Lina-Marcela
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Bottai, Matteo
    Karolinska Inst, Inst Environm Med, Unit Biostat, SE-17176 Stockholm, Sweden..
    Nennesmo, Inger
    Karolinska Inst, Dept Lab Med, SE-17176 Stockholm, Sweden..
    Chemin, Karine
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Herrath, Jessica
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Johansson, Karin
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Wikberg, Anders
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Ytterberg, A. Jimmy
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, SE-17176 Stockholm, Sweden..
    Zubarev, Roman A.
    Karolinska Inst, Dept Med Biochem & Biophys, SE-17176 Stockholm, Sweden..
    Danielsson, Olof
    Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, Div Neurol, Linkoping, Sweden..
    Krystufkova, Olga
    Charles Univ Prague, Fac Med 1, Inst Rheumatol, Prague, Czech Republic.;Charles Univ Prague, Fac Med 1, Dept Rheumatol, Prague, Czech Republic..
    Vencovsky, Jiri
    Charles Univ Prague, Fac Med 1, Inst Rheumatol, Prague, Czech Republic.;Charles Univ Prague, Fac Med 1, Dept Rheumatol, Prague, Czech Republic..
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Dept Med Solna, Expt Endocrinol, SE-17176 Stockholm, Sweden..
    Wahren-Herlenius, Marie
    Karolinska Inst, Dept Med Solna, Expt Rheumatol Unit, SE-17176 Stockholm, Sweden..
    Padyukov, Leonid
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Dept Med Solna, Expt Endocrinol, SE-17176 Stockholm, Sweden..
    Lundberg, Ingrid E.
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies2015In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 125, no 12, p. 4612-4624Article in journal (Refereed)
    Abstract [en]

    Mutations of the gene encoding four-and-a-half LIM domain 1 (FHL1) are the causative factor of several X-linked hereditary myopathies that are collectively termed FHL1-related myopathies. These disorders are characterized by severe muscle dysfunction and damage. Here, we have shown that patients with idiopathic inflammatory myopathies (IIMs) develop autoimmunity to FHL1, which is a muscle-specific protein. Anti-FHL1 autoantibodies were detected in 25% of IIM patients, while patients with other autoimmune diseases or muscular dystrophies were largely anti-FHL1 negative. Anti-FHL1 reactivity was predictive for muscle atrophy, dysphagia, pronounced muscle fiber damage, and vasculitis. FHL1 showed an altered expression pattern, with focal accumulation in the muscle fibers of autoantibody-positive patients compared with a homogeneous expression in anti-FHL1-negative patients and healthy controls. We determined that FHL1 is a target of the cytotoxic protease granzyme B, indicating that the generation of FHL1 fragments may initiate FHL1 autoimmunity. Moreover, immunization of myositis-prone mice with FHL1 aggravated muscle weakness and increased mortality, suggesting a direct link between anti-FHL1 responses and muscle damage. Together, our findings provide evidence that FHL1 may be involved in the pathogenesis not only of genetic FHL1-related myopathies but also of autoimmune IIM. Importantly, these results indicate that anti-FHL1 autoantibodies in peripheral blood have promising potential as a biomarker to identify a subset of severe IIM.

  • 2. Aspelund, Aleksanteri
    et al.
    Tammela, Tuomas
    Antila, Salli
    Nurmi, Harri
    Leppanen, Veli-Matti
    Zarkada, Georgia
    Stanczuk, Lukas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Francois, Mathias
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Saharinen, Pipsa
    Immonen, Ilkka
    Alitalo, Kari
    The Schlemm's canal is a VEGF-C/VEGFR-3-responsive lymphatic-like vessel2014In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 124, no 9, p. 3975-3986Article in journal (Refereed)
    Abstract [en]

    In glaucoma, aqueous outflow into the Schlemm's canal (SC) is obstructed. Despite striking structural and functional similarities with the lymphatic vascular, system, it is unknown whether the SC is a blood or lymphatic vessel. Here, we demonstrated the expression of lymphatic endothelial cell markers by the SC in murine and zebrafish models as well as in human eye tissue. The initial stages of SC development involved induction of the transcription factor PROX1 and the lymphangiogenic receptor tyrosine kinase VEGFR-3 in venous endothelial cells in postnatal mice. Using gene deletion and function-blocking antibodies in mice, we determined that the lymphangiogenic growth factor VEGF-C and its receptor, VEGFR-3, are essential for SC development. Delivery of VEGF-C into the adult eye resulted in sprouting, proliferation, and growth of SC endothelial cells, whereas VEGF-A obliterated the aqueous outflow system. Furthermore, a single injection of recombinant VEGF-C induced SC growth and was associated with trend toward a sustained decrease in intraocular pressure in adult mice. These results reveal the evolutionary conservation of the lymphatic-like phenotype of the SC, implicate VEGF-C and VEGFR-3 as critical regulators of SC lymphangiogenesis, and provide a basis for further studies on therapeutic manipulation of the SC with VEGF-C in glaucoma treatment.

  • 3. Bazigou, Eleni
    et al.
    Lyons, Oliver T A
    Smith, Alberto
    Venn, Graham E
    Cope, Celia
    Brown, Nigel A
    Makinen, Taija
    Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice.2011In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 121, no 8Article in journal (Refereed)
    Abstract [en]

    Chronic venous disease and venous hypertension are common consequences of valve insufficiency, yet the molecular mechanisms regulating the formation and maintenance of venous valves have not been studied. Here, we provide what we believe to be the first description of venous valve morphogenesis and identify signaling pathways required for the process. The initial stages of valve development were found to involve induction of ephrin-B2, a key marker of arterial identity, by venous endothelial cells. Intriguingly, developing and mature venous valves also expressed a repertoire of proteins, including prospero-related homeobox 1 (Prox1), Vegfr3, and integrin-α9, previously characterized as specific and critical regulators of lymphangiogenesis. Using global and venous valve-selective knockout mice, we further demonstrate the requirement of ephrin-B2 and integrin-α9 signaling for the development and maintenance of venous valves. Our findings therefore identified molecular regulators of venous valve development and maintenance and highlighted the involvement of common morphogenetic processes and signaling pathways in controlling valve formation in veins and lymphatic vessels. Unexpectedly, we found that venous valve endothelial cells closely resemble lymphatic (valve) endothelia at the molecular level, suggesting plasticity in the ability of a terminally differentiated endothelial cell to take on a different phenotypic identity.

  • 4. Bode, Lars
    et al.
    Salvestrini, Camilla
    Park, Pyong Woo
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Esko, Jeffrey D
    Yamaguchi, Yu
    Murch, Simon
    Freeze, Hudson H
    Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function2008In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 118, no 1, p. 229-238Article in journal (Refereed)
    Abstract [en]

    Patients with protein-losing enteropathy (PLE) fail to maintain intestinal epithelial barrier function and develop an excessive and potentially fatal efflux of plasma proteins. PLE occurs in ostensibly unrelated diseases, but emerging commonalities in clinical observations recently led us to identify key players in PLE pathogenesis. These include elevated IFN-gamma, TNF-alpha, venous hypertension, and the specific loss of heparan sulfate proteoglycans from the basolateral surface of intestinal epithelial cells during PLE episodes. Here we show that heparan sulfate and syndecan-1, the predominant intestinal epithelial heparan sulfate proteoglycan, are essential in maintaining intestinal epithelial barrier function. Heparan sulfate- or syndecan-1-deficient mice and mice with intestinal-specific loss of heparan sulfate had increased basal protein leakage and were far more susceptible to protein loss induced by combinations of IFN-gamma, TNF-alpha, and increased venous pressure. Similarly, knockdown of syndecan-1 in human epithelial cells resulted in increased basal and cytokine-induced protein leakage. Clinical application of heparin has been known to alleviate PLE in some patients but its unknown mechanism and severe side effects due to its anticoagulant activity limit its usefulness. We demonstrate here that non-anticoagulant 2,3-de-O-sulfated heparin could prevent intestinal protein leakage in syndecan-deficient mice, suggesting that this may be a safe and effective therapy for PLE patients.

  • 5. Chen, Chiu-Yu
    et al.
    Bertozzi, Cara
    Zou, Zhiying
    Yuan, Lijun
    Lee, John S
    Lu, MinMin
    Stachelek, Stan J
    Srinivasan, Sathish
    Guo, Lili
    Vicente, Andres
    Mericko, Patricia
    Levy, Robert J
    Makinen, Taija
    Oliver, Guillermo
    Kahn, Mark L
    Blood flow reprograms lymphatic vessels to blood vessels.2012In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 122, no 6Article in journal (Refereed)
    Abstract [en]

    Human vascular malformations cause disease as a result of changes in blood flow and vascular hemodynamic forces. Although the genetic mutations that underlie the formation of many human vascular malformations are known, the extent to which abnormal blood flow can subsequently influence the vascular genetic program and natural history is not. Loss of the SH2 domain-containing leukocyte protein of 76 kDa (SLP76) resulted in a vascular malformation that directed blood flow through mesenteric lymphatic vessels after birth in mice. Mesenteric vessels in the position of the congenital lymphatic in mature Slp76-null mice lacked lymphatic identity and expressed a marker of blood vessel identity. Genetic lineage tracing demonstrated that this change in vessel identity was the result of lymphatic endothelial cell reprogramming rather than replacement by blood endothelial cells. Exposure of lymphatic vessels to blood in the absence of significant flow did not alter vessel identity in vivo, but lymphatic endothelial cells exposed to similar levels of shear stress ex vivo rapidly lost expression of PROX1, a lymphatic fate-specifying transcription factor. These findings reveal that blood flow can convert lymphatic vessels to blood vessels, demonstrating that hemodynamic forces may reprogram endothelial and vessel identity in cardiovascular diseases associated with abnormal flow.

  • 6. Crowley, Steven D
    et al.
    Vasievich, Matthew P
    Ruiz, Phillip
    Gould, Samantha K
    Parsons, Kelly K
    Pazmino, A Kathy
    Facemire, Carie
    Chen, Benny J
    Kim, Hyung-Suk
    Tran, Trinh T
    Pisetsky, David S
    Barisoni, Laura
    Prieto-Carrasquero, Minolfa C
    Jeansson, Marie
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Foster, Mary H
    Coffman, Thomas M
    Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis2009In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 119, no 4, p. 943-53Article in journal (Refereed)
    Abstract [en]

    Studies in humans and animal models indicate a key contribution of angiotensin II to the pathogenesis of glomerular diseases. To examine the role of type 1 angiotensin (AT1) receptors in glomerular inflammation associated with autoimmune disease, we generated MRL-Faslpr/lpr (lpr) mice lacking the major murine type 1 angiotensin receptor (AT1A); lpr mice develop a generalized autoimmune disease with glomerulonephritis that resembles SLE. Surprisingly, AT1A deficiency was not protective against disease but instead substantially accelerated mortality, proteinuria, and kidney pathology. Increased disease severity was not a direct effect of immune cells, since transplantation of AT1A-deficient bone marrow did not affect survival. Moreover, autoimmune injury in extrarenal tissues, including skin, heart, and joints, was unaffected by AT1A deficiency. In murine systems, there is a second type 1 angiotensin receptor isoform, AT1B, and its expression is especially prominent in the renal glomerulus within podocytes. Further, expression of renin was enhanced in kidneys of AT1A-deficient lpr mice, and they showed evidence of exaggerated AT1B receptor activation, including substantially increased podocyte injury and expression of inflammatory mediators. Administration of losartan, which blocks all type 1 angiotensin receptors, reduced markers of kidney disease, including proteinuria, glomerular pathology, and cytokine mRNA expression. Since AT1A-deficient lpr mice had low blood pressure, these findings suggest that activation of type 1 angiotensin receptors in the glomerulus is sufficient to accelerate renal injury and inflammation in the absence of hypertension.

  • 7. de Luca, Carl
    et al.
    Kowalski, Timothy J
    Zhang, Yiying
    Elmquist, Joel K
    Lee, Charlotte
    Kilimann, Manfred W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Ludwig, Thomas
    Liu, Shun-Mei
    Chua, Streamson C
    Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes2005In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 115, no 12, p. 3484-3493Article in journal (Refereed)
    Abstract [en]

    We have generated mice that carry a neuron-specific leptin receptor (LEPR) transgene whose expression is driven by the rat synapsin I promoter synapsin-LEPR B (SYN-LEPR-B). We have also generated mice that are compound hemizygotes for the transgenes SYN-LEPR-B and neuron-specific enolase-LEPR B (NSE-LEPR-B). We observed a degree of correction in db/db mice that are hemizygous (Syn db/db) and homozygous (Syn/Syn db/db) for the SYN-LEPR-B transgene similar to that previously reported for the NSE-LEPR-B transgene. We also show complete correction of the obesity and related phenotypes of db/db mice that are hemizygous for both NSE-LEPR-B and SYN-LEPR-B transgenes (Nse+Syn db/db). Body composition, insulin sensitivity, and cold tolerance were completely normalized in Nse+Syn db/db mice at 12 weeks of age compared with lean controls. In situ hybridization for LEPR B isoform expression in Nse+Syn db/db mice showed robust expression in the energy homeostasis-relevant regions of the hypothalamus. Expression of 3 neuropeptide genes, agouti-related peptide (Agrp), neuropeptide Y (Npy), and proopiomelanocortin (Pomc), was fully normalized in dual transgenic db/db mice. The 2 transgenes in concert conferred normal fertility to male and female db/db mice. Male mice with partial peripheral deletion of Lepr, induced in the periweaning phase, did not show alterations in body composition or mass. In summary, we show that brain-specific leptin signaling is sufficient to reverse the obesity, diabetes, and infertility of db/db mice.

  • 8.
    Elgendy, Mohamed
    et al.
    European Inst Oncol IEO, Dept Expt Oncol, Milan, Italy.;Univ Vienna, Max F Perutz Labs, Dept Microbiol & Immunobiol, Dr Bohr Gasse 9, A-1030 Vienna, Austria..
    Abdel-Aziz, Amal Kamal
    European Inst Oncol IEO, Dept Expt Oncol, Milan, Italy.;Ain Shams Univ, Dept Pharmacol & Toxicol, Fac Pharm, Cairo, Egypt..
    Renne, Salvatore Lorenzo
    Fdn IRCCS Ist Nazl Tumori, Dept Pathol & Lab Med, Milan, Italy..
    Bornaghi, Viviana
    European Inst Oncol IEO, Dept Expt Oncol, Milan, Italy..
    Procopio, Giuseppe
    Fdn IRCCS Ist Nazl Tumori, Genitourinary Oncol Unit, Milan, Italy..
    Colecchia, Maurizio
    Fdn IRCCS Ist Nazl Tumori, Dept Pathol & Lab Med, Milan, Italy..
    Kanesvaran, Ravindran
    Natl Canc Ctr Singapore, Div Med Oncol, Singapore, Singapore.;Duke NUS Med Sch, Singapore, Singapore..
    Toh, Chee Keong
    Natl Canc Ctr Singapore, Div Med Oncol, Singapore, Singapore..
    Bossi, Daniela
    European Inst Oncol IEO, Dept Expt Oncol, Milan, Italy..
    Pallavicini, Isabella
    European Inst Oncol IEO, Dept Expt Oncol, Milan, Italy..
    Luis Perez-Gracia, Jose
    Univ Navarra Clin, Dept Oncol, Pamplona, Spain..
    Dolores Lozano, Maria
    Univ Navarra Clin, Dept Pathol, Pamplona, Spain..
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Mercurio, Ciro
    IFOM, Unit Expt Therapies, Milan, Italy..
    Lanfrancone, Luisa
    European Inst Oncol IEO, Dept Expt Oncol, Milan, Italy..
    Fazio, Nicola
    European Inst Oncol, Unit Gastrointestinal Med Oncol & Neuroendocrine, Milan, Italy..
    Nole, Franco
    IEO, Dept Clin Oncol, Milan, Italy..
    Teh, Bin Tean
    Duke NUS Med Sch, Singapore, Singapore.;Natl Canc Ctr Singapore, Div Med Sci, Singapore, Singapore.;Canc Sci Inst, Singapore, Singapore.;Inst Mol & Cell Biol, Singapore, Singapore..
    Renne, Giuseppe
    Dept Pathol IEO, Milan, Italy..
    Minucci, Saverio
    European Inst Oncol IEO, Dept Expt Oncol, Milan, Italy.;Univ Milan, Dept Biosci, Milan, Italy.;IEO, Drug Dev Program, Milan, Italy..
    Dual modulation of MCL-1 and mTOR determines the response to sunitinib2017In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 127, no 1, p. 153-168Article in journal (Refereed)
    Abstract [en]

    Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of the contribution of sunitinib's numerous targets to the clinical response or to resistance is crucial. Here, we have shown that cancer cells respond to clinically relevant doses of sunitinib by enhancing the stability of the antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition of MCL-1 or mTORC1 signaling sensitized cells to clinically relevant doses of sunitinib in vitro and was synergistic with sunitinib in impairing tumor growth in vivo, indicating that these responses are triggered as prosurvival mechanisms that enable cells to tolerate the cytotoxic effects of sunitinib. Furthermore, higher doses of sunitinib were cytotoxic, triggered a decline in MCL-1 levels, and inhibited mTORC1 signaling. Mechanistically, we determined that sunitinib modulates MCL-1 stability by affecting its proteasomal degradation. Dual modulation of MCL-1 stability at different dose ranges of sunitinib was due to differential effects on ERK and GSK3 beta activity, and the latter also accounted for dual modulation of mTORC1 activity. Finally, comparison of patient samples prior to and following sunitinib treatment suggested that increases in MCL-1 levels and mTORC1 activity correlate with resistance to sunitinib in patients.

  • 9. Elkabets, Moshe
    et al.
    Gifford, Ann M.
    Scheel, Christina
    Nilsson, Björn
    Reinhardt, Ferenc
    Bray, Mark-Anthony
    Carpenter, Anne E.
    Jirström, Karin
    Magnusson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Ebert, Benjamin L.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Weinberg, Robert A.
    McAllister, Sandra S.
    Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice2011In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 121, no 2, p. 784-799Article in journal (Refereed)
    Abstract [en]

    Systemic instigation is a process by which endocrine signals sent from certain tumors (instigators) stimulate BM cells (BMCs), which are mobilized into the circulation and subsequently foster the growth of otherwise indolent carcinoma cells (responders) residing at distant anatomical sites. The identity of the BMCs and their specific contribution or contributions to responder tumor growth have been elusive. Here, we have demonstrated that Scal(+)cKit(-) hematopoietic BMCs of mouse hosts bearing instigating tumors promote the growth of responding tumors that form with a myofibroblast-rich, desmoplastic stroma. Such stroma is almost always observed in malignant human adenocarcinomas and is an indicator of poor prognosis. We then identified granulin (GRN) as the most upregulated gene in instigating Scal(+)cKit(-) BMCs relative to counterpart control cells. The GRN(+) BMCs that were recruited to the responding tumors induced resident tissue fibroblasts to express genes that promoted malignant tumor progression; indeed, treatment with recombinant GRN alone was sufficient to promote desmoplastic responding tumor growth. Further, analysis of tumor tissues from a cohort of breast cancer patients revealed that high GRN expression correlated with the most aggressive triple-negative, basal-like tumor subtype and reduced patient survival. Our data suggest that GRN and the unique hematopoietic BMCs that produce it might serve as novel therapeutic targets.

  • 10.
    Fischer, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Harvima, Ilkka T..
    Carvalho, Ricardo F. S.
    Möller, Christine
    Naukkarinen, Anita
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nilsson, Gunnar
    Mast cell CD30 ligand is upregulated in cutaneous inflammation and mediates degranulation-independent chemokine secretion2006In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 116, no 10, p. 2748-2756Article in journal (Refereed)
    Abstract [en]

    Mast cells are involved in many disorders where the triggering mechanism that leads to degranulation and/or cytokine secretion has not been defined. Several chronic inflammatory diseases are associated with increased mast cell numbers and upregulation of the TNF receptor family member CD30, but the role of elevated CD30 expression is poorly understood. Here we report what we believe to be a novel way to activate mast cells with CD30 that leads to degranulation-independent secretion of chemokines. CD30 induced a de novo synthesis and secretion of the chemokines IL-8, macrophage inflammatory protein-1 alpha (MIP-1 alpha), and MIP-1 beta, a process involving the MAPK/ERK pathway. Mast cells were found to be the predominant CD30 ligand-positive (CD30L-positive) cell in the chronic inflammatory skin diseases psoriasis and atopic dermatitis, and both CD30 and CD30L expression were upregulated in lesional skin in these conditions. Furthermore, the number of IL-8-positive mast cells was elevated both in psoriatic and atopic dermatitis lesional skin as well as in ex vivo CD30-treated healthy skin organ cultures. In summary, characterization of CD30 activation of mast cells has uncovered an IgE-independent pathway that is of importance in understanding the entirety of the role of mast cells in diseases associated with mast cells and CD30 expression. These diseases include Hodgkin lymphoma, atopic dermatitis, and psoriasis.

  • 11.
    Gandasi, Nikhil R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Yin, Peng
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Riz, Michela
    Univ Padua, Dept Informat Engn, Padua, Italy..
    Chibalina, Margarita V
    Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Cortese, Giuliana
    Univ Padua, Dept Stat Sci, Padua, Italy..
    Lund, Per-Eric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Matveev, Victor
    New Jersey Inst Technol, Dept Math Sci, Newark, NJ 07102 USA..
    Rorsman, Patrik
    Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Sherman, Arthur
    NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA..
    Pedersen, Morten G
    Univ Padua, Dept Informat Engn, Padua, Italy..
    Barg, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ca2+ channel clustering with insulin-containing granules is disturbed in type 2 diabetes2017In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 127, no 6, p. 2353-2364Article in journal (Refereed)
    Abstract [en]

    Loss of first-phase insulin secretion is an early sign of developing type 2 diabetes (T2D). Ca2+ entry through voltage-gated L-type Ca2+ channels triggers exocytosis of insulin-containing granules in pancreatic β cells and is required for the postprandial spike in insulin secretion. Using high-resolution microscopy, we have identified a subset of docked insulin granules in human β cells and rat-derived clonal insulin 1 (INS1) cells for which localized Ca2+ influx triggers exocytosis with high probability and minimal latency. This immediately releasable pool (IRP) of granules, identified both structurally and functionally, was absent in β cells from human T2D donors and in INS1 cells cultured in fatty acids that mimic the diabetic state. Upon arrival at the plasma membrane, IRP granules slowly associated with 15 to 20 L-type channels. We determined that recruitment depended on a direct interaction with the synaptic protein Munc13, because expression of the II-III loop of the channel, the C2 domain of Munc13-1, or of Munc13-1 with a mutated C2 domain all disrupted L-type channel clustering at granules and ablated fast exocytosis. Thus, rapid insulin secretion requires Munc13-mediated recruitment of L-type Ca2+ channels in close proximity to insulin granules. Loss of this organization underlies disturbed insulin secretion kinetics in T2D.

  • 12. Hess, Paul R
    et al.
    Rawnsley, David R
    Jakus, Zoltán
    Yang, Yiqing
    Sweet, Daniel T
    Fu, Jianxin
    Herzog, Brett
    Lu, MinMin
    Nieswandt, Bernhard
    Oliver, Guillermo
    Makinen, Taija
    Xia, Lijun
    Kahn, Mark L
    Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life.2014In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 124, no 1Article in journal (Refereed)
    Abstract [en]

    Mammals transport blood through a high-pressure, closed vascular network and lymph through a low-pressure, open vascular network. These vascular networks connect at the lymphovenous (LV) junction, where lymph drains into blood and an LV valve (LVV) prevents backflow of blood into lymphatic vessels. Here we describe an essential role for platelets in preventing blood from entering the lymphatic system at the LV junction. Loss of CLEC2, a receptor that activates platelets in response to lymphatic endothelial cells, resulted in backfilling of the lymphatic network with blood from the thoracic duct (TD) in both neonatal and mature mice. Fibrin-containing platelet thrombi were observed at the LVV and in the terminal TD in wild-type mice, but not Clec2-deficient mice. Analysis of mice lacking LVVs or lymphatic valves revealed that platelet-mediated thrombus formation limits LV backflow under conditions of impaired valve function. Examination of mice lacking integrin-mediated platelet aggregation indicated that platelet aggregation stabilizes thrombi that form in the lymphatic vascular environment to prevent retrograde blood flow. Collectively, these studies unveil a newly recognized form of hemostasis that functions with the LVV to safeguard the lymphatic vascular network throughout life.

  • 13. Iglesias, José
    et al.
    Barg, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vallois, David
    Lahiri, Shawon
    Roger, Catherine
    Yessoufou, Akadiri
    Pradevand, Sylvain
    McDonald, Angela
    Bonal, Claire
    Reimann, Frank
    Gribble, Fiona
    Debril, Marie-Bernard
    Metzger, Daniel
    Chambon, Pierre
    Herrera, Pedro
    Rutter, Guy A
    Prentki, Marc
    Thorens, Bernard
    Wahli, Walter
    PPARβ/δ affects pancreatic β cell mass and insulin secretion in mice2012In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 122, no 11, p. 4105-4117Article in journal (Refereed)
    Abstract [en]

    PPARβ/δ protects against obesity by reducing dyslipidemia and insulin resistance via effects in muscle, adipose tissue, and liver. However, its function in pancreas remains ill defined. To gain insight into its hypothesized role in β cell function, we specifically deleted Pparb/d in the epithelial compartment of the mouse pancreas. Mutant animals presented increased numbers of islets and, more importantly, enhanced insulin secretion, causing hyperinsulinemia. Gene expression profiling of pancreatic β cells indicated a broad repressive function of PPARβ/δ affecting the vesicular and granular compartment as well as the actin cytoskeleton. Analyses of insulin release from isolated PPARβ/δ-deficient islets revealed an accelerated second phase of glucose-stimulated insulin secretion. These effects in PPARβ/δ-deficient islets correlated with increased filamentous actin (F-actin) disassembly and an elevation in protein kinase D activity that altered Golgi organization. Taken together, these results provide evidence for a repressive role for PPARβ/δ in β cell mass and insulin exocytosis, and shed a new light on PPARβ/δ metabolic action.

  • 14. Iovino, Federico
    et al.
    Hammarlöf, Disa L.
    Garriss, Genevieve
    Brovall, Sarah
    Nannapaneni, Priyanka
    Henriques-Normark, Birgitta
    Pneumococcal meningitis is promoted by single cocci expressing pilus adhesin RrgA2016In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 126, no 8, p. 2821-2826Article in journal (Refereed)
    Abstract [en]

    Streptococcus pneumoniae (pneumococcus) is the primary cause of bacterial meningitis. Pneumococcal bacteria penetrates the blood-brain barrier (BBB), but the bacterial factors that enable this process are not known. Here, we determined that expression of pneumococcal pilus-1, which includes the pilus adhesin RrgA, promotes bacterial penetration through the BBB in a mouse model. S. pneumoniae that colonized the respiratory epithelium and grew in the bloodstream were chains of variable lengths; however, the pneumococci that entered the brain were division-competent, spherical, single cocci that expressed adhesive RrgA-containing pili. The cell division protein DivIVA, which is required for an ovoid shape, was localized at the poles and septum of pneumococcal chains of ovoid, nonseparated bacteria, but was absent in spherical, single cocci. In the bloodstream, a small percentage of pneumococci appeared as piliated, RrgA-expressing, DivIVA-negative single cocci, suggesting that only a minority of S. pneumoniae are poised to cross the BBB. Together, our data indicate that small bacterial cell size, which is signified by the absence of DivIVA, and the presence of an adhesive RrgA-containing pilus-1 mediate pneumococcal passage from the bloodstream through the BBB into the brain to cause lethal meningitis.

  • 15.
    Jeansson, Marie
    et al.
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hopsital.
    Gawlik, Alexander
    Anderson, Gregory
    Li, Chengjin
    Kerjaschki, Dontscho
    Henkelman, Mark
    Quaggin, Susan E
    Angiopoietin-1 is essential in mouse vasculature during development and in response to injury2011In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 121, no 6, p. 2278-2289Article in journal (Refereed)
    Abstract [en]

    Angiopoietin-1/Tek signaling is a critical regulator of blood vessel development, with conventional knockout of angiopoietin-1 or Tek in mice being embryonically lethal due to vascular defects. In addition, angiopoietin-1 is thought to be required for the stability of mature vessels. Using a Cre-Lox conditional gene targeting approach, we have studied the role of angiopoietin-1 in embryonic and adult vasculature. We report here that angiopoietin-1 is critical for regulating both the number and diameter of developing vessels but is not required for pericyte recruitment. Cardiac-specific knockout of angiopoietin-1 reproduced the phenotype of the conventional knockout, demonstrating that the early vascular abnormalities arise from flow-dependent defects. Strikingly, deletion in the entire embryo after day E13.5 produced no immediate vascular phenotype. However, when combined with injury or microvascular stress, angiopoietin-1 deficiency resulted in profound organ damage, accelerated angiogenesis, and fibrosis. These findings redefine our understanding of the biological roles of angiopoietin-1: it is dispensable in quiescent vessels but has a powerful ability to modulate the vascular response after injury.

  • 16.
    Klar, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hisatsune, Chihiro
    Baig, Shahid M.
    Tariq, Muhammad
    Johansson, Anna C. V.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Rasool, Mahmood
    Malik, Naveed Altaf
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sugiura, Kotomi
    Feuk, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Mikoshiba, Katsuhiko
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Abolished InsP3R2 function inhibits sweat secretion in both humans and mice2014In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 124, no 11, p. 4773-4780Article in journal (Refereed)
    Abstract [en]

    There are 3 major sweat-producing glands present in skin; eccrine, apocrine, and apoeccrine glands. Due to the high rate of secretion, eccrine sweating is a vital regulator of body temperature in response to thermal stress in humans; therefore, an inability to sweat (anhidrosis) results in heat intolerance that may cause impaired consciousness and death. Here, we have reported 5 members of a consanguineous family with generalized, isolated anhidrosis, but morphologically normal eccrine sweat glands. Whole-genome analysis identified the presence of a homozygous missense mutation in ITPR2, which encodes the type 2 inositol 1,4,5-trisphosphate receptor (InsP3R2), that was present in all affected family members. We determined that the mutation is localized within the pore forming region of InsP3R2 and abrogates Ca2+ release from the endoplasmic reticulum, which suggests that intracellular Ca2+ release by InsP3R2 in clear cells of the sweat glands is important for eccrine sweat production. Itpr2–/– mice exhibited a marked reduction in sweat secretion, and evaluation of sweat glands from Itpr2–/– animals revealed a decrease in Ca2+ response compared with controls. Together, our data indicate that loss of InsP3R2-mediated Ca2+ release causes isolated anhidrosis in humans and suggest that specific InsP3R inhibitors have the potential to reduce sweat production in hyperhidrosis.

  • 17. Knowles, Joshua W.
    et al.
    Xie, Weijia
    Zhang, Zhongyang
    Chennemsetty, Indumathi
    Assimes, Themistocles L.
    Paananen, Jussi
    Hansson, Ola
    Pankow, James
    Goodarzi, Mark O.
    Carcamo-Orive, Ivan
    Morris, Andrew P.
    Chen, Yii-Der I.
    Maekinen, Ville-Petteri
    Ganna, Andrea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mahajan, Anubha
    Guo, Xiuqing
    Abbasi, Fahim
    Greenawalt, Danielle M.
    Lum, Pek
    Molony, Cliona
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lindgren, Cecilia
    Raffel, Leslie J.
    Tsao, Philip S.
    Schadt, Eric E.
    Rotter, Jerome I.
    Sinaiko, Alan
    Reaven, Gerald
    Yang, Xia
    Hsiung, Chao A.
    Groop, Leif
    Cordell, Heather J.
    Laakso, Markku
    Hao, Ke
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Frayling, Timothy M.
    Weedon, Michael N.
    Walker, Mark
    Quertermous, Thomas
    Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene2015In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 125, no 4, p. 1739-1751Article in journal (Refereed)
    Abstract [en]

    Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.

  • 18. Koivisto, U M
    et al.
    Turtola, H
    Aalto-Setälä, K
    Top, B
    Frants, R R
    Kovanen, P T
    Syvänen, Ann-Christine
    Kontula, K
    The familial hypercholesterolemia (FH)-North Karelia mutation of the low density lipoprotein receptor gene deletes seven nucleotides of exon 6 and is a common cause of FH in Finland1992In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 90, no 1, p. 219-228Article in journal (Refereed)
    Abstract [en]

    A mutation of the LDL receptor gene very common among Finnish patients with heterozygous familial hypercholesterolemia (FH) was identified. This mutation, designated as FH-North Karelia, deletes seven nucleotides from exon 6 of the LDL receptor gene, causes a translational frameshift, and is predicted to result in a truncated receptor protein. Only minute quantities of mRNA corresponding to the deleted gene were detected. Functional studies using cultured fibroblasts from the patients revealed that the FH-North Karelia gene is associated with a receptor-negative (or binding-defective) phenotype of FH. Carriers of the FH-North Karelia gene showed a typical xanthomatous form of FH, with mean serum total and LDL cholesterol levels of 12 and 10 mmol/liter, respectively. This mutation was found in 69 (34%) out of 201 nonrelated Finnish FH patients and was especially abundant (prevalence 79%) in patients from the eastern Finland. These results, combined with our earlier data on another LDL receptor gene deletion (FH-Helsinki), demonstrate that two "Finnish-type" mutant LDL receptor genes make up about two thirds of FH mutations in this country, reflecting a founder gene effect. This background provides good possibilities to examine whether genetic heterogeneity affects the clinical presentation or responsiveness to therapeutic interventions in FH.

  • 19. Li, Xuri
    et al.
    Tjwa, Marc
    Moons, Lieve
    Fons, Pierre
    Noel, Agnes
    Ny, Annelii
    Zhou, Jian Min
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Li, Hong
    Luttun, Aernout
    Pontén, Annica
    Devy, Laetitia
    Bouché, Ann
    Oh, Hideyasu
    Manderveld, Ann
    Blacher, Silvia
    Communi, David
    Savi, Pierre
    Bono, Françoise
    Dewerchin, Mieke
    Foidart, Jean-Michel
    Autiero, Monica
    Herbert, Jean-Marc
    Collen, D
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Eriksson, Ulf
    Carmeliet, Peter
    Revascularization of ischemic tissues by PDGF-CC via effects on endothelial cells and their progenitors2005In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 115, no 1, p. 118-127Article in journal (Refereed)
    Abstract [en]

    The angiogenic mechanism and therapeutic potential of PDGF-CC, a recently discovered member of the VEGF/PDGF superfamily, remain incompletely characterized. Here we report that PDGF-CC mobilized endothelial progenitor cells in ischemic conditions; induced differentiation of bone marrow cells into ECs; and stimulated migration of ECs. Furthermore, PDGF-CC induced the differentiation of bone marrow cells into smooth muscle cells and stimulated their growth during vessel sprouting. Moreover, delivery of PDGF-CC enhanced postischemic revascularization of the heart and limb. Modulating the activity of PDGF-CC may provide novel opportunities for treating ischemic diseases.

  • 20.
    Li, Yang
    et al.
    National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.
    Zhang, Fan
    National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.
    Nagai, Nobuo
    Department of Physiology, Kinki University School of Medicine, Osakasayama, Osaka, Japan.
    Tang, Zhongshu
    National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.
    Zhang, Shuihua
    National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.
    Scotney, Pierre
    CSL Limited, Parkville, Victoria, Australia.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Zhu, Chaoyong
    National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.
    Qu, Yi
    National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.
    Fang, Changge
    National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.
    Hua, Jianyuan
    National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.
    Matsuo, Osamu
    Department of Physiology, Kinki University School of Medicine, Osakasayama, Osaka, Japan.
    Fong, Guo-Hua
    Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut, USA.
    Ding, Hao
    Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
    Cao, Yihai
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden..
    Becker, Kevin G
    TRIAD Technology Center, National Institute on Aging, NIH, Baltimore, Maryland, USA.
    Nash, Andrew
    CSL Limited, Parkville, Victoria, Australia.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Li, Xuri
    National Eye Institute, NIH, Porter Neuroscience Research Center, Bethesda, Maryland, USA.
    VEGF-B inhibits apoptosis via VEGFR-1-mediated suppression of the expression of BH3-only protein genes in mice and rats.2008In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 118, no 3, p. 913-923Article in journal (Refereed)
    Abstract [en]

    Despite its early discovery and high sequence homology to the other VEGF family members, the biological functions of VEGF-B remain poorly understood. We revealed here a novel function for VEGF-B as a potent inhibitor of apoptosis. Using gene expression profiling of mouse primary aortic smooth muscle cells, and confirming the results by real-time PCR using mouse and rat cell lines, we showed that VEGF-B inhibited the expression of genes encoding the proapoptotic BH3-only proteins and other apoptosis- and cell death-related proteins, including p53 and members of the caspase family, via activation of VEGFR-1. Consistent with this, VEGF-B treatment rescued neurons from apoptosis in the retina and brain in mouse models of ocular neurodegenerative disorders and stroke, respectively. Interestingly, VEGF-B treatment at the dose effective for neuronal survival did not cause retinal neovascularization, suggesting that VEGF-B is the first member of the VEGF family that has a potent antiapoptotic effect while lacking a general angiogenic activity. These findings indicate that VEGF-B may potentially offer a new therapeutic option for the treatment of neurodegenerative diseases.

  • 21. Liu, Kui
    et al.
    Li, Quan-Zhen
    Delgado-Vega, Angelica M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Abelson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sánchez, Elena
    Kelly, Jennifer A.
    Li, Li
    Liu, Yang
    Zhou, Jinchun
    Yan, Mei
    Ye, Qiu
    Liu, Shenxi
    Xie, Chun
    Zhou, Xin J.
    Chung, Sharon A.
    Pons-Estel, Bernardo
    Witte, Torsten
    de Ramón, Enrique
    Bae, Sang-Cheol
    Barizzone, Nadia
    Sebastiani, Gian Domenico
    Merrill, Joan T.
    Gregersen, Peter K.
    Gilkeson, Gary G.
    Kimberly, Robert P.
    Vyse, Timothy J.
    Kim, Il
    D'Alfonso, Sandra
    Martin, Javier
    Harley, John B.
    Criswell, Lindsey A.
    Wakeland, Edward K.
    Alarcón-Riquelme, Marta E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mohan, Chandra
    Danieli, M.G.
    Galeazzi, M.
    Querini, P.R.
    Migliaresi, S.
    Scherbarth, H.R.
    Lopez, J.A.
    Motta, E.L.
    Gamron, S.
    Drenkard, C.
    Menso, E.
    Allievi, A.
    Tate, G.A.
    Presas, J.L.
    Palatnik, S.A.
    Abdala, M.
    Bearzotti, M.
    Alvarellos, A.
    Caeiro, F.
    Bertoli, A.
    Paira, S.
    Roverano, S.
    Graf, C.E.
    Bertero, E.
    Caprarulo, C.
    Buchanan, G.
    Guillerón, C.
    Grimaudo, S.
    Manni, J.
    Catoggio, L.J.
    Soriano, E.R.
    Santos, C.D.
    Prigione, C.
    Ramos, F.A.
    Navarro, S.M.
    Berbotto, G.A.
    Jorfen, M.
    Romero, E.J.
    Garcia, M.A.
    Marcos, J.C.
    Marcos, A.I.
    Perandones, C.E.
    Eimon, A.
    Battagliotti, C.G.
    Armadi-Simab, K.
    Gross, W.L.
    Gromica-Ihle, E.
    Peter, H.H.
    Manger, K.
    Schnarr, S.
    Zeidler, H.
    Schmidt, R.E.
    Ortego, N.
    Callejas, J.L.
    Jiménez-Alonso, J.
    Sabio, M.
    Sánchez-Román, J.
    Garcia-Hernandez, F.J.
    Camps, M.
    López-Nevot, M.A.
    González-Escribano, M.F.
    Harley, J.H.
    Riquelme, M.A.
    Kimberly, R.
    Criswell, L.
    Langefeld, C.
    Tsao, B.
    Jacob, C.
    Kallikrein genes are associated with lupus and glomerular basement membrane-specific antibody-induced nephritis in mice and humans2009In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 119, no 4, p. 911-923Article in journal (Refereed)
    Abstract [en]

    Immune-mediated nephritis contributes to disease in systemic lupus erythematosus, Goodpasture syndrome (caused by antibodies specific for glomerular basement membrane [anti-GBM antibodies]), and spontaneous lupus nephritis. Inbred mouse strains differ in susceptibility to anti-GBM antibody-induced and spontaneous lupus nephritis. This study sought to clarify the genetic and molecular factors that maybe responsible for enhanced immune-mediated renal disease in these models. When the kidneys of 3 mouse strains sensitive to anti-GBM antibody-induced nephritis were compared with those of 2 control strains using microarray analysis, one-fifth of the underexpressed genes belonged to the kallikrein gene family,which encodes serine esterases. Mouse strains that upregulated renal and urinary kallikreins exhibited less evidence of disease. Antagonizing the kallikrein pathway augmented disease, while agonists dampened the severity of anti-GBM antibody-induced nephritis. In addition, nephritis-sensitive mouse strains had kallikrein haplotypes that were distinct from those of control strains, including several regulatory polymorphisms,some of which were associated with functional consequences. Indeed, increased susceptibility to anti-GBM antibody-induced nephritis and spontaneous lupus nephritis was achieved by breeding mice with a genetic interval harboring the kallikrein genes onto a disease-resistant background. Finally, both human SLE and spontaneous lupus nephritis were found to be associated with kallikrein genes, particularly KLK1 and the KLK3 promoter, when DNA SNPs from independent cohorts of SLE patients and controls were compared. Collectively, these studies suggest that kallikreins are protective disease-associated genes in anti-GBM antibody-induced nephritis and lupus.

  • 22.
    Lugano, Roberta
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Vemuri, Kalyani
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dejana, Elisabetta
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Dimberg, Anna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis.2018In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 128, no 8, p. 3280-3297Article in journal (Refereed)
    Abstract [en]

    Tumor angiogenesis occurs through regulation of genes that orchestrate endothelial sprouting and vessel maturation, including deposition of a vessel-associated extracellular matrix. CD93 is a transmembrane receptor that is up-regulated in tumor vessels in many cancers, including high-grade glioma. Here, we demonstrate that CD93 regulates integrin-β1-signaling and organization of fibronectin fibrillogenesis during tumor vascularization. In endothelial cells and mouse retina, CD93 was found to be expressed in endothelial filopodia and to promote filopodia formation. The CD93 localization to endothelial filopodia was stabilized by interaction with multimerin-2 (MMRN2), which inhibited its proteolytical cleavage. The CD93-MMRN2 complex was required for activation of integrin-β1, phosphorylation of focal adhesion kinase (FAK) and fibronectin fibrillogenesis in endothelial cells. Consequently, tumor vessels in gliomas implanted orthotopically in CD93-deficient mice showed diminished activation of integrin-β1 and lacked organization of fibronectin into fibrillar structures. These findings demonstrate a key role of CD93 in vascular maturation and organization of the extracellular matrix in tumors, identifying it as a potential target for therapy.

  • 23.
    Martin-Almedina, Silvia
    et al.
    St Georges Univ London, Cardiovasc & Cell Sci Inst, Lymphovasc Res Unit, Cranmer Terrace, London SW17 0RE, England..
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Holdhus, Rita
    Univ Bergen, Dept Clin Sci, Genom Core Facil, Bergen, Norway..
    Vicente, Andres
    Canc Res UK London Res Inst, Lymphat Dev Lab, London, England.;UCL Inst Neurol, Dept Clin & Expt Epilepsy, Queen Sq, London, England..
    Fotiou, Elisavet
    St Georges Univ London, Cardiovasc & Cell Sci Inst, Lymphovasc Res Unit, Cranmer Terrace, London SW17 0RE, England..
    Lin, Shin
    Stanford Univ, Div Cardiovasc Med, Stanford, CA 94305 USA.;Stanford Univ, Dept Genet, Stanford, CA 94305 USA..
    Petersen, Kjell
    Univ Bergen, Dept Informat, Computat Biol Unit, Bergen, Norway..
    Simpson, Michael A.
    Kings Coll London, Guys Hosp, Sch Med, Div Genet & Mol Med, London, England..
    Hoischen, Alexander
    Univ Bergen, Dept Clin Sci, Genom Core Facil, Bergen, Norway.;Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Donders Ctr Neurosci, Nijmegen, Netherlands..
    Gilissen, Christian
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Donders Ctr Neurosci, Nijmegen, Netherlands..
    Jeffery, Heather
    St Georges Univ London, Cardiovasc & Cell Sci Inst, Lymphovasc Res Unit, Cranmer Terrace, London SW17 0RE, England..
    Atton, Giles
    St Georges Univ London, South West Thames Reg Genet Unit, London, England..
    Karapouliou, Christina
    St Georges Univ London, Cardiovasc & Cell Sci Inst, Lymphovasc Res Unit, Cranmer Terrace, London SW17 0RE, England..
    Brice, Glen
    St Georges Univ London, South West Thames Reg Genet Unit, London, England..
    Gordon, Kristiana
    St Georges Univ Hosp NHS Fdn Trust, Dept Dermatol, London, England..
    Wiseman, John W.
    AstraZeneca R&D, RAD Transgen, Discovery Sci, Molndal, Sweden..
    Wedin, Marianne
    AstraZeneca R&D, RAD Transgen, Discovery Sci, Molndal, Sweden..
    Rockson, Stanley G.
    Stanford Univ, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Jeffery, Steve
    St Georges Univ London, Cardiovasc & Cell Sci Inst, Lymphovasc Res Unit, Cranmer Terrace, London SW17 0RE, England..
    Mortimer, Peter S.
    St Georges Univ London, Cardiovasc & Cell Sci Inst, Lymphovasc Res Unit, Cranmer Terrace, London SW17 0RE, England..
    Snyder, Michael P.
    Stanford Univ, Dept Genet, Stanford, CA 94305 USA..
    Berland, Siren
    Haukeland Hosp, Ctr Med Genet & Mol Med, Bergen, Norway..
    Mansour, Sahar
    St Georges Univ London, South West Thames Reg Genet Unit, London, England..
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ostergaard, Pia
    St Georges Univ London, Cardiovasc & Cell Sci Inst, Lymphovasc Res Unit, Cranmer Terrace, London SW17 0RE, England..
    EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis2016In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 126, no 8, p. 3080-3088Article in journal (Refereed)
    Abstract [en]

    Hydrops fetalis describes fluid accumulation in at least 2 fetal compartments, including abdominal cavities, pleura, and pericardium, or in body tissue. The majority of hydrops fetalis cases are nonimmune conditions that present with generalized edema of the fetus, and approximately 15% of these nonimmune cases result from a lymphatic abnormality. Here, we have identified an autosomal dominant, inherited form of lymphatic-related (nonimmune) hydrops fetalis (LRHF). Independent exome sequencing projects on 2 families with a history of in utero and neonatal deaths associated with nonimmune hydrops fetalis uncovered 2 heterozygous missense variants in the gene encoding Eph receptor B4 (EPHB4). Biochemical analysis determined that the mutant EPHB4 proteins are devoid of tyrosine kinase activity, indicating that loss of EPHB4 signaling contributes to LRHF pathogenesis. Further, inactivation of Ephb4 in lymphatic endothelial cells of developing mouse embryos led to defective lymphovenous valve formation and consequent subcutaneous edema. Together, these findings identify EPHB4 as a critical regulator of early lymphatic vascular development and demonstrate that mutations in the gene can cause an autosomal dominant form of LRHF that is associated with a high mortality rate.

  • 24. Park, Dae-Young
    et al.
    Lee, Junyeop
    Park, Intae
    Choi, Dongwon
    Lee, Sunju
    Song, Sukhyun
    Hwang, Yoonha
    Hong, Ki Yong
    Nakaoka, Yoshikazu
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Kim, Pilhan
    Alitalo, Kari
    Hong, Young-Kwon
    Koh, Gou Young
    Lymphatic regulator PROX1 determines Schlemm's canal integrity and identity2014In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 124, no 9, p. 3960-3974Article in journal (Refereed)
    Abstract [en]

    Schlemm's canal (SC) is a specialized vascular structure in the eye that functions to drain aqueous humor from the intraocular chamber into systemic circulation. Dysfunction of SC has been proposed to Underlie increased aqueous humor outflow (AHO) resistance, which leads to elevated ocular pressure, a factor for glaucoma development in humans. Here, using lymphatic and blood vasculature reporter mice, we determined that SC, which originates from blood vessels during the postnatal period, acquires lymphatic identity through upregulation of prospero homeobox protein 1 (PROX1), the master regulator of lymphatic development. SC expressed lymphatic valve markers FOXC2 and integrin alpha(9) and exhibited continuous vascular endothelial-cadherin (VE-cadherin) junctions and basement membrane, similar to collecting lymphatics. SC notably lacked luminal valves and expression of the lymphatic endothelial cell markers podoplanin and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1). Using an ocular puncture model, we determined that reduced AHO altered the fate of SC both during development and under pathologic conditions; however, alteration of VEGF-C/VEGFR3 signaling did not modulate SC integrity and identity. Intriguingly, PROX1 expression levels linearly correlated with SC functionality. For example, PROX1 expression was reduced or undetectable under pathogenic conditions and in deteriorated SCs. Collectively, our data indicate that PROX1 is an accurate and reliable biosensor of SC integrity and identity.

  • 25.
    Reuterdahl, C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Sundberg, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Funa, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Gerdin, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Tissue localization of beta receptors for platelet-derived growth factor and platelet-derived growth factor B chain during wound repair in humans1993In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 91, no 5, p. 2065-2075Article in journal (Refereed)
    Abstract [en]

    The expression and localization of PDGF beta receptors and PDGF-AB/BB in human healing wounds was evaluated by immunohistochemical techniques and in situ hybridization. Expression of PDGF beta receptor protein and PDGF-AB/BB were analyzed in wound margin biopsies using the PDGFR-B2 and PDGF 007 antibodies. PDGF beta receptor expression was minor in normal skin. An increased expression of PDGF beta receptor protein was prominent in vessels in the proliferating tissue zone in wounds as early as 1 d after surgery and was apparent < or = 4 wk after surgery. There was also a concordant increase in PDGF beta receptor mRNA detected by in situ hybridization. PDGF-AB/BB was present in healing wounds as well as in normal skin. In normal skin, expression of PDGF-AB/BB was confined to peripheral nerve fibers and to solitary cells of the epidermis and of the superficial dermis. In wounds, infiltrating mononuclear cells also stained for PDGF-AB/BB. To identify cell types expressing PDGF AB/BB and PDGF beta receptors, respectively, we performed double immunofluorescence stainings. PDGF beta receptors were expressed by vascular smooth muscle cells and cells in capillary walls; the receptor protein could not be detected in neurofilament containing structures, T lymphocytes, or CD68 expressing macrophages. PDGF-AB/BB colocalized with neurofilaments, it was present in Langerhans cells of the epidermis and in HLA-DR positive cells located in the epidermal/dermal junction area. Of the macrophages infiltrating the wound, 43 +/- 18% stained positively for PDGF AB/BB. Since PDGF-AB/BB and PDGF beta receptors are expressed in the healing wound, two essential prerequisites for a role of PDGF in wound healing are fulfilled.

  • 26.
    Sabine, Amelie
    et al.
    CHUV, Dept Fundamental Oncol, CH-1066 Epalinges, Switzerland.;Univ Lausanne, CH-1066 Epalinges, Switzerland..
    Bovay, Esther
    CHUV, Dept Fundamental Oncol, CH-1066 Epalinges, Switzerland.;Univ Lausanne, CH-1066 Epalinges, Switzerland..
    Demir, Cansaran Saygili
    CHUV, Dept Fundamental Oncol, CH-1066 Epalinges, Switzerland.;Univ Lausanne, CH-1066 Epalinges, Switzerland..
    Kimura, Wataru
    Hamamatsu Univ Sch Med, Hamamatsu, Shizuoka 4313192, Japan..
    Jaquet, Muriel
    CHUV, Dept Fundamental Oncol, CH-1066 Epalinges, Switzerland.;Univ Lausanne, CH-1066 Epalinges, Switzerland..
    Agalarov, Yan
    CHUV, Dept Fundamental Oncol, CH-1066 Epalinges, Switzerland.;Univ Lausanne, CH-1066 Epalinges, Switzerland..
    Zangger, Nadine
    SIB, Lausanne, Switzerland..
    Scallan, Joshua P.
    Univ Missouri, Columbia, MO USA..
    Graber, Werner
    Univ Bern, Inst Anat, Bern, Switzerland..
    Gulpinar, Elgin
    Harvard Univ, Cambridge, MA USA..
    Kwak, Brenda R.
    Univ Geneva, Dept Pathol & Immunol, Geneva, Switzerland.;Univ Geneva, Dept Med Specializat Cardiol, Geneva, Switzerland..
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Martinez-Corral, Ines
    Spanish Natl Canc Res Ctr, Madrid, Spain..
    Ortega, Sagrario
    Spanish Natl Canc Res Ctr, Madrid, Spain..
    Delorenzi, Mauro
    SIB, Lausanne, Switzerland.;Univ Lausanne, Ludwig Ctr Canc Res, Lausanne, Switzerland..
    Kiefer, Friedemann
    Max Planck Inst Mol Biomed, D-48149 Munster, Germany..
    Davis, Michael J.
    Univ Missouri, Columbia, MO USA..
    Djonov, Valentin
    Univ Bern, Inst Anat, Bern, Switzerland..
    Miura, Naoyuld
    Hamamatsu Univ Sch Med, Hamamatsu, Shizuoka 4313192, Japan..
    Petrova, Tatiana V.
    CHUV, Dept Fundamental Oncol, CH-1066 Epalinges, Switzerland.;Univ Lausanne, CH-1066 Epalinges, Switzerland.;Ecole Polytech Fed Lausanne, Swiss Canc Res Inst, Lausanne, Switzerland..
    FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature2015In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 125, no 10, p. 3861-3877Article in journal (Refereed)
    Abstract [en]

    Biomechanical forces, such as fluid shear stress, govern multiple aspects of endothelial cell biology. In blood vessels, disturbed flow is associated with vascular diseases, such as atherosclerosis, and promotes endothelial cell proliferation and apoptosis. Here, we identified an important role for disturbed flow in lymphatic vessels, in which it cooperates with the transcription factor FOXC2 to ensure lifelong stability of the lymphatic vasculature. In cultured lymphatic endothelial cells, FOXC2 inactivation conferred abnormal shear stress sensing, promoting junction disassembly and entry into the cell cycle. Loss of FOXC2-dependent quiescence was mediated by the Hippo pathway transcriptional coactivator TAZ and, ultimately, led to cell death. In murine models, inducible deletion of Foxc2 within the lymphatic vasculature led to cell-cell junction defects, regression of valves, and focal vascular lumen collapse, which triggered generalized lymphatic vascular dysfunction and lethality. Together, our work describes a fundamental mechanism by which FOXC2 and oscillatory shear stress maintain lymphatic endothelial cell quiescence through intercellular junction and cytoskeleton stabilization and provides an essential link between biomechanical forces and endothelial cell identity that is necessary for postnatal vessel homeostasis. As FOXC2 is mutated in lymphedema-distichiasis syndrome, our data also underscore the role of impaired mechanotransduction in the pathology of this hereditary human disease.

  • 27. Thomson, Benjamin R
    et al.
    Heinen, Stefan
    Jeansson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Ghosh, Asish K
    Fatima, Anees
    Sung, Hoon-Ki
    Onay, Tuncer
    Chen, Hui
    Yamaguchi, Shinji
    Economides, Aris N
    Flenniken, Ann
    Gale, Nicholas W
    Hong, Young-Kwon
    Fawzi, Amani
    Liu, Xiaorong
    Kume, Tsutomu
    Quaggin, Susan E
    A lymphatic defect causes ocular hypertension and glaucoma in mice2014In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 124, no 10, p. 4320-4324Article in journal (Refereed)
    Abstract [en]

    Glaucoma is a leading cause of blindness, afflicting more than 60 million people worldwide. Increased intraocular pressure (IOP) due to impaired aqueous humor drainage is a major risk factor for the development of glaucoma. Here, we demonstrated that genetic disruption of the angiopoietin/TIE2 (ANGPT/TIE2) signaling pathway results in high IOP, buphthalmos, and classic features of glaucoma, including retinal ganglion degeneration and vision loss. Eyes from mice with induced deletion of Angpt1 and Angpt2 (A1A2FloxWB mice) lacked drainage pathways in the corneal limbus, including Schlemm’s canal and lymphatic capillaries, which share expression of the PROX1, VEGFR3, and FOXC family of transcription factors. VEGFR3 and FOXCs have been linked to lymphatic disorders in patients, and FOXC1 has been linked to glaucoma. In contrast to blood endothelium, in which ANGPT2 is an antagonist of ANGPT1, we have shown that both ligands cooperate to regulate TIE2 in the lymphatic network of the eye. While A1A2FloxWB mice developed high IOP and glaucoma, expression of ANGPT1 or ANGPT2 alone was sufficient for ocular drainage. Furthermore, we demonstrated that loss of FOXC2 from lymphatics results in TIE2 downregulation, suggesting a mechanism for ocular defects in patients with FOXC mutations. These data reveal a pathogenetic and molecular basis for glaucoma and demonstrate the importance of angiopoietin ligand cooperation in the lymphatic endothelium.

  • 28.
    Tisch, Nathalie
    et al.
    Heidelberg Univ, Biochem Ctr, Heidelberg, Germany;Heidelberg Univ, European Ctr Angiosci ECAS, Heidelberg, Germany;Heidelberg Univ, Med Fac Mannheim, Inst Transfus Med & Immunol, Heidelberg, Germany.
    Freire-Valls, Aida
    Heidelberg Univ, Biochem Ctr, Heidelberg, Germany;Heidelberg Univ, Med Fac Mannheim, Dept Gen Visceral & Transplantat Surg, Heidelberg, Germany.
    Yerbes, Rosario
    Heidelberg Univ, Biochem Ctr, Heidelberg, Germany;Univ Seville, CSIC, Ctr Andaluz Biol Mol & Med Regenerat CABIMER, Seville, Spain;Univ Pablo Olavide, Seville, Spain.
    Paredes, Isidora
    Heidelberg Univ, Biochem Ctr, Heidelberg, Germany;Heidelberg Univ, European Ctr Angiosci ECAS, Heidelberg, Germany;Heidelberg Univ, Med Fac Mannheim, Inst Transfus Med & Immunol, Heidelberg, Germany.
    La Porta, Silvia
    Heidelberg Univ, European Ctr Angiosci ECAS, Heidelberg, Germany;German Canc Res Ctr, Div Vasc Oncol & Metastasis, Heidelberg, Germany.
    Wang, Xiaohong
    Heidelberg Univ, Biochem Ctr, Heidelberg, Germany.
    Martin-Perez, Rosa
    Ctr Canc Biol VIB, Lab Tumor Inflammat & Angiogenesis, Leuven, Belgium;Katholieke Univ Leuven, Dept Oncol, Lab Tumor Inflammat & Angiogenesis, Leuven, Belgium.
    Castro, Laura
    Heidelberg Univ, Biochem Ctr, Heidelberg, Germany.
    Wong, Wendy Wei-Lynn
    Univ Zurich, Inst Expt Immunol, Zurich, Switzerland.
    Coultas, Leigh
    Walter & Eliza Hall Inst Med Res, Dev & Canc Div, Parkville, Vic, Australia;Univ Melbourne, Dept Med Biol, Melbourne, Vic, Australia.
    Strilic, Boris
    Max Planck Inst Heart & Lung Res, Dept Pharmacol, Bad Nauheim, Germany.
    Gröne, Hermann-Josef
    German Canc Res Ctr, Dept Cellular & Mol Pathol, Heidelberg, Germany.
    Hielscher, Thomas
    German Canc Res Ctr, Div Biostat, Heidelberg, Germany.
    Mogler, Carolin
    Tech Univ Munich, TUM Sch Med, Inst Pathol, Munich, Germany.
    Adams, Ralf H.
    Max Planck Inst Mol Biomed, Dept Tissue Morphogenesis, Munster, Germany;Univ Munster, Univ Med Ctr, Fac Med, Munster, Germany.
    Heiduschka, Peter
    Univ Munster, Univ Med Ctr, Dept Ophthalmol, Res Lab, Munster, Germany.
    Claesson-Welsh, Lena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Mazzone, Massimiliano
    Ctr Canc Biol VIB, Lab Tumor Inflammat & Angiogenesis, Leuven, Belgium;Katholieke Univ Leuven, Dept Oncol, Lab Tumor Inflammat & Angiogenesis, Leuven, Belgium.
    Lopez-Rivas, Abelardo
    Univ Seville, CSIC, Ctr Andaluz Biol Mol & Med Regenerat CABIMER, Seville, Spain;Univ Pablo Olavide, Seville, Spain;Carlos III Hlth Inst, Ctr Invest Biomed Red Oncol CIBERONC, Madrid, Spain.
    Schmidt, Thomas
    Heidelberg Univ, Med Fac Mannheim, Dept Gen Visceral & Transplantat Surg, Heidelberg, Germany.
    Augustin, Hellmut G.
    Heidelberg Univ, European Ctr Angiosci ECAS, Heidelberg, Germany;German Canc Res Ctr, Div Vasc Oncol & Metastasis, Heidelberg, Germany.
    Ruiz de Almodovar, Carmen
    Heidelberg Univ, Biochem Ctr, Heidelberg, Germany;Heidelberg Univ, European Ctr Angiosci ECAS, Heidelberg, Germany;Heidelberg Univ, Med Fac Mannheim, Inst Transfus Med & Immunol, Heidelberg, Germany.
    Caspase-8 modulates physiological and pathological angiogenesis during retina development2019In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 129, no 12, p. 5092-5107Article in journal (Refereed)
    Abstract [en]

    During developmental angiogenesis, blood vessels grow and remodel to ultimately build a hierarchical vascular network. Whether, how, cell death signaling molecules contribute to blood vessel formation is still not well understood. Caspase-8 (Casp-8), a key protease in the extrinsic cell death-signaling pathway, regulates cell death via both apoptosis and necroptosis. Here, we show that expression of Casp-8 in endothelial cells (ECs) is required for proper postnatal retina angiogenesis. EC-specific Casp-8-KO pups (Casp-8(ECKO)) showed reduced retina angiogenesis, as the loss of Casp-8 reduced EC proliferation, sprouting, and migration independently of its cell death function. Instead, the loss of Casp-8 caused hyperactivation of p38 MAPK downstream of receptor-interacting serine/threonine protein kinase 3 (RIPK3) and destabilization of vascular endothelial cadherin (VE-cadherin) at EC junctions. In a mouse model of oxygen-induced retinopathy (OIR) resembling retinopathy of prematurity (ROP), loss of Casp-8 in ECs was beneficial, as pathological neovascularization was reduced in Casp-8ECKO pups. Taking these data together, we show that Casp-8 acts in a cell death-independent manner in ECs to regulate the formation of the retina vasculature and that Casp-8 in ECs is mechanistically involved in the pathophysiology of ROP.

  • 29. Wennbo, Håkan
    et al.
    Gebre-Medhin, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Gritli-Linde, Amel
    Ohlsson, Claes
    Isaksson, Olle G. P.
    Törnell, Jan
    Activation of the prolactin receptor but not the growth hormone receptor is important for induction of mammary tumors in transgenic mice1997In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 100, no 11, p. 2744-2751Article in journal (Refereed)
    Abstract [en]

    Transgenic mice overexpressing the human growth hormone gene develop mammary carcinomas. Since human growth hormone gene can activate both the growth hormone receptor (GHR) and the prolactin (PRL) receptor (PRLR), it is not clear which receptor system is responsible for the malignant transformation. To clarify the receptor specificity, we created transgenic mice with two different genes: (a) transgenic mice overexpressing the bovine growth hormone (bGH) gene having high levels of bGH only activating the GHR and also high serum levels of IGF-I; and (b) transgenic mice overexpressing the rat PRL (rPRL) gene that have elevated levels of PRL (one line 150 ng/ml and one line 13 ng/ml) only binding to the PRLR and with normal IGF-I levels. When analyzed histologically, all of the PRL transgenic female mice developed mammary carcinomas at 11-15 mo of age. Only normal mammary tissue was observed among the bGH transgenic animals and the controls. Cell lines established from a tumor produced rPRL and expressed PRLR. In organ culture experiments, an auto/paracrine effect of rPRL was demonstrated. In conclusion, activation of the PRLR is sufficient for induction of mammary carcinomas in mice, while activation of the GHR is not sufficient for mammary tumor formation.

  • 30.
    Wild, Philipp S.
    et al.
    Prevent Cardiol & Prevent Med, Dept Med 2, Beijing, Peoples R China.;Johannes Gutenberg Univ Mainz, Univ Med Ctr, Ctr Thrombosis & Hemostasis, Mainz, Germany.;DZHK German Ctr Cardiovasc Res Partner Site Rhine, Mainz, Germany.;Johannes Gutenberg Univ Mainz, Univ Med Ctr, Ctr Cardiol, Langen beckstr 1, D-55131 Mainz, Germany.;Johannes Gutenberg Univ Mainz, Univ Med Ctr, Ctr Thrombosis & Hemostasis, Langen beckstr 1, D-55131 Mainz, Germany..
    Felix, Janine F.
    Univ Med Ctr Rotterdam, Dept Epidemiol, Erasmus MC, Rotterdam, Netherlands.;Univ Med Ctr Rotterdam, Dept Epidemiol, Erasmus MC, Room Na 2906,POB 2040, NL-3000 CA Rotterdam, Netherlands..
    Schillert, Arne
    Univ Lubeck, Univ Med Ctr Schleswig Holstein, Inst Med Biometry & Stat, Lubeck, Germany.;DZHK Partner Site Hamburg Kiel Lubeck, Hamburg, Germany..
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany.;DZHK Partner Site Greifswald, Greifswald, Germany..
    Chen, Ming-Huei
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA..
    Leening, Maarten J. G.
    Univ Med Ctr Rotterdam, Dept Epidemiol, Erasmus MC, Rotterdam, Netherlands.;Univ Med Ctr Rotterdam, Dept Cardiol, Erasmus MC, Rotterdam, Netherlands..
    Voelker, Uwe
    DZHK Partner Site Greifswald, Greifswald, Germany.;Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany..
    Grossmann, Vera
    Johannes Gutenberg Univ Mainz, Univ Med Ctr, Ctr Thrombosis & Hemostasis, Mainz, Germany..
    Brody, Jennifer A.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA..
    Irvin, Marguerite R.
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA..
    Shah, Sanjiv J.
    Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA..
    Pramana, Setia
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Lieb, Wolfgang
    Christian Albrechts Univ Kiel, Inst Epidemiol & Popgen Biobank, Kiel, Germany..
    Schmidt, Reinhold
    Med Univ Graz, Dept Neurol, Clin Div Neurogeriatr, Graz, Austria..
    Stanton, Alice V.
    Beaumont Hosp, Blood Pressure Unit, Dublin, Ireland.;Royal Coll Surgeons Ireland, Dept Mol & Cellular Therapeut, Dublin, Ireland..
    Malzahn, Doerthe
    Georg August Univ, Univ Med Ctr, Dept Genet Epidemiol, Gottingen, Germany..
    Smith, Albert Vernon
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Minelli, Cosetta
    Imperial Coll London, Natl Heart & Lung Inst NHLI, Populat Hlth & Occupat Dis, London, England..
    Ruggiero, Daniela
    Inst Genet & Biophys A Buzzati Traverso, CNR, Naples, Italy..
    Lyytikainen, Leo-Pekka
    Dept Clin Chem, Fimlab Labs, Tampere, Finland.;Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Tampere, Finland..
    Tiller, Daniel
    Martin Luther Univ Halle Wittenberg, Inst Med Epidemiol, Biostat & Informat, Halle, Germany..
    Smith, J. Gustav
    Lund Univ, Dept Cardiol, Lund, Sweden.;Skane Univ Hosp, Lund, Sweden.;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Harvard Med Sch, Boston, MA USA..
    Monnereau, Claire
    Univ Med Ctr Rotterdam, Dept Epidemiol, Erasmus MC, Rotterdam, Netherlands.;Generat R Study Grp, Rotterdam, Netherlands.;Univ Med Ctr Rotterdam, Dept Pediat, Erasmus MC, Rotterdam, Netherlands..
    Di Tullio, Marco R.
    Columbia Univ, Med Ctr, Dept Med, New York, NY USA..
    Musani, Solomon K.
    Univ Mississippi, Med Ctr, Jackson Heart Study, Jackson, MS 39216 USA..
    Morrison, Alanna C.
    Univ Texas Hlth Sci Ctr Houston, Dept Epidemiol, Human Genet & Environm Sci, Houston, TX USA..
    Pers, Tune H.
    Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA USA.;Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA.;Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.;Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark..
    Morley, Michael
    Univ Penn, Perelman Sch Med, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA.;Univ Penn, Perelman Sch Med, Div Cardiovasc Med, Philadelphia, PA 19104 USA..
    Kleber, Marcus E.
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany..
    Aragam, Jayashri
    Harvard Med Sch, Boston, MA USA.;Vet Adm Hosp, West Roxbury, Boston, MA USA..
    Benjamin, Emelia J.
    Natl Heart Lung & Blood Inst, Framingham, MA USA.;Boston Univ Framingham Heart Study, Framingham, MA USA.;Boston Univ, Sch Med & Publ Hlth, Sect Cardiol, Prevent Med & Epidemiol, Boston, MA USA..
    Bis, Joshua C.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA..
    Bisping, Egbert
    Med Univ Graz, Dept Cariol, Graz, Austria..
    Broeckel, Ulrich
    Med Coll Wisconsin, Milwaukee, WI 53226 USA..
    Cheng, Susan
    Natl Heart Lung & Blood Inst, Framingham, MA USA.;Boston Univ Framingham Heart Study, Framingham, MA USA.;Harvard Med Sch, Brigham & Womens Hosp, Cardiovasc Div, Boston, MA USA..
    Deckers, Jaap W.
    Univ Med Ctr Rotterdam, Dept Cardiol, Erasmus MC, Rotterdam, Netherlands..
    Del Greco, Fabiola
    Univ Lubeck, European Acad Bolzano Bozen, Ctr Biomed, Lubeck, Germany.;Univ Lubeck, Affiliated Inst, Lubeck, Germany..
    Edelmann, Frank
    Charite Univ Med Berlin, Dept Cardiol, Campus Virchow Klinikum, Berlin, Germany..
    Fornage, Myriam
    Univ Texas Hlth Sci Ctr, Houston, TX USA..
    Franke, Lude
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Friedrich, Nele
    DZHK Partner Site Greifswald, Greifswald, Germany.;Univ Med Greifswald, Inst Clin Chem, Greifswald, Germany.;Univ Med Greifswald, Lab Med, Greifswald, Germany..
    Harris, Tamara B.
    Natl Inst Aging, NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD USA..
    Hofer, Edith
    Med Univ Graz, Dept Neurol, Clin Div Neurogeriatr, Graz, Austria.;Med Univ Graz, Inst Med Informat, Stat & Documentat, Graz, Austria..
    Hofman, Albert
    Univ Med Ctr Rotterdam, Dept Epidemiol, Erasmus MC, Rotterdam, Netherlands..
    Huang, Jie
    Boston VA Res Inst, Boston, MA USA.;Harvard Med Sch, Brigham & Womens Hosp, Div Aging, Boston, MA USA..
    Hughes, Alun D.
    UCL, Inst Cardiovasc Sci, London, England..
    Kahonen, Mika
    Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland.;Univ Tampere, Fac Med & Life Sci, Dept Clin Physiol, Tampere, Finland..
    Kruppa, Jochen
    Univ Lubeck, Univ Med Ctr Schleswig Holstein, Inst Med Biometry & Stat, Lubeck, Germany.;Univ Vet Med, Fdn Inst Vet Med & Genet, Hannover, Germany..
    Lackner, Karl J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Univ Med Ctr Mainz, Inst Clin Chem & Lab Med, Mainz, Germany.
    Lannfelt, Lars
    Univ Med Ctr Mainz, Dept Med 2, Mainz, Germany..
    Laskowski, Rafael
    Univ Med Ctr Mainz, Dept Med 2, Mainz, Germany..
    Launer, Lenore J.
    Natl Inst Aging, NIH, Neuroepidemiol Sect, Bethesda, MD USA..
    Leosdottir, Margret
    Lund Univ, Dept Cardiol, Lund, Sweden.;Skane Univ Hosp, Malmo, Sweden..
    Lin, Honghuang
    Natl Heart Lung & Blood Inst, Framingham, MA USA.;Boston Univ Framingham Heart Study, Framingham, MA USA.;Boston Univ, Sch Med, Dept Med, Sect Computat Biomed, Boston, MA 02215 USA..
    Lindgren, Cecilia M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;MIT, Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA..
    Loley, Christina
    Univ Lubeck, Univ Med Ctr Schleswig Holstein, Inst Med Biometry & Stat, Lubeck, Germany..
    MacRae, Calum A.
    MIT, Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA.;Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA..
    Mascalzoni, Deborah
    Univ Lubeck, European Acad Bolzano Bozen, Ctr Biomed, Lubeck, Germany.;Univ Lubeck, Affiliated Inst, Lubeck, Germany..
    Mayet, Jamil
    Hammersmith Hosp, Int Ctr Circulatory Hlth, London, England.;NHLI, Imperial Coll London, London, England..
    Medenwald, Daniel
    Martin Luther Univ Halle Wittenberg, Inst Med Epidemiol, Biostat & Informat, Halle, Germany..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England..
    Mueller, Christian
    Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, Hamburg, Germany..
    Mueller-Nurasyid, Martina
    Ludwig Maximilians Univ Munchen, Dept Med 1, Munich, Germany.;DZHK Partner Site Munich Heart Alliance, Munich, Germany.;Inst Genet Epidemiol, Helmholtz Zentrum Munchen German Res Ctr Environm, Neuherberg, Germany..
    Nappo, Stefania
    Inst Genet & Biophys A Buzzati Traverso, CNR, Naples, Italy..
    Nilsson, Peter M.
    Lund Univ, Dept Clin Sci, Malmo, Sweden.;Skane Univ Hosp, Dept Internal Med, Malmo, Sweden..
    Nuding, Sebastian
    Univ Clin Halle Saale, Martin Luther Univ Halle Wittenberg, Dept Med 3, Halle, Germany..
    Nutile, Teresa
    Inst Genet & Biophys A Buzzati Traverso, CNR, Naples, Italy..
    Peters, Annette
    DZHK Partner Site Munich Heart Alliance, Munich, Germany.;Inst Epidemiol II, Helmholtz Zentrum Munchen German Res Ctr Environm, Neuherberg, Germany..
    Pfeufer, Arne
    Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Pietzner, Diana
    Martin Luther Univ Halle Wittenberg, Inst Med Epidemiol, Biostat & Informat, Halle, Germany..
    Pramstaller, Peter P.
    Univ Lubeck, European Acad Bolzano Bozen, Ctr Biomed, Lubeck, Germany.;Univ Lubeck, Affiliated Inst, Lubeck, Germany.;Gen Cent Hosp, Dept Neurol, Bolzano, Italy.;Univ Lubeck, Dept Neurol, Lubeck, Germany..
    Raitakari, Olli T.
    Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland.;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland..
    Rice, Kenneth M.
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Rivadeneira, Fernando
    Univ Med Ctr Rotterdam, Dept Epidemiol, Erasmus MC, Rotterdam, Netherlands.;Generat R Study Grp, Rotterdam, Netherlands.;Univ Med Ctr Rotterdam, Dept Internal Med, Erasmus MC, Rotterdam, Netherlands..
    Rotter, Jerome I.
    Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA USA..
    Ruohonen, Saku T.
    Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland..
    Sacco, Ralph L.
    Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL USA.;Univ Miami, Miller Sch Med, McKnight Brain Inst Miller, Miami, FL USA.;Univ Miami, Dept Publ Hlth Sci, Miami, FL USA.;Univ Miami, Dept Human Gen, Miami, FL USA..
    Samdarshi, Tandaw E.
    Univ Mississippi, Med Ctr, Div Cardiol, Jackson, MS 39216 USA..
    Schmidt, Helena
    Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria..
    Sharp, Andrew S. P.
    Royal Devon & Exeter Hosp & Univ Exeter, Dept Cardiol, Exeter, Devon, England..
    Shields, Denis C.
    Univ Coll Dublin, UCD Conway Inst Biomol & Biomed Res, Dublin, Ireland.;Univ Coll Dublin, Sch Med & Med Sci, Dublin, Ireland..
    Sorice, Rossella
    Inst Genet & Biophys A Buzzati Traverso, CNR, Naples, Italy.;IRCCS Neuromed, Pozzilli, Isernia, Italy..
    Sotoodehnia, Nona
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.;Univ Washington, Div Cardiol, Seattle, WA 98195 USA..
    Stricker, Bruno H.
    Univ Med Ctr Rotterdam, Dept Epidemiol, Erasmus MC, Rotterdam, Netherlands.;Univ Med Ctr Rotterdam, Dept Internal Med, Erasmus MC, Rotterdam, Netherlands.;Inspectorate Hlth Care, Utrecht, Netherlands..
    Surendran, Praveen
    Royal Coll Surgeons Ireland, Dept Mol & Cellular Therapeut, Dublin, Ireland.;Univ Coll Dublin, Sch Med & Med Sci, Dublin, Ireland..
    Thom, Simon
    Hammersmith Hosp, Int Ctr Circulatory Hlth, London, England.;NHLI, Imperial Coll London, London, England..
    Toeglhofer, Anna M.
    Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria..
    Uitterlinden, Andre G.
    Univ Med Ctr Rotterdam, Dept Epidemiol, Erasmus MC, Rotterdam, Netherlands.;Univ Med Ctr Rotterdam, Dept Internal Med, Erasmus MC, Rotterdam, Netherlands..
    Wachter, Rolf
    Georg August Univ, Univ Med Ctr Gottingen, Dept Cardiol & Pneumol, Gottingen, Germany..
    Voelzke, Henry
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany.;DZHK Partner Site Greifswald, Greifswald, Germany..
    Ziegler, Andreas
    Univ Lubeck, Univ Med Ctr Schleswig Holstein, Inst Med Biometry & Stat, Lubeck, Germany.;DZHK Partner Site Hamburg Kiel Lubeck, Hamburg, Germany.;Univ KwaZulu Natal, Sch Math, Stat & Comp Sci, Durban, South Africa.;Univ Lubeck, Zentrum Klin Studien, Lubeck, Germany..
    Muenzel, Thomas
    DZHK German Ctr Cardiovasc Res Partner Site Rhine, Mainz, Germany.;Univ Med Ctr Mainz, Dept Med 2, Mainz, Germany..
    Maerz, Winfried
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany.;Synlab Acad, Synlab Serv GmbH, Mannheim, Germany.;Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria..
    Cappola, Thomas P.
    Univ Penn, Perelman Sch Med, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA.;Univ Penn, Perelman Sch Med, Div Cardiovasc Med, Philadelphia, PA 19104 USA..
    Hirschhorn, Joel N.
    Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA USA.;Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA.;Harvard Med Sch, Dept Genet, Boston, MA USA..
    Mitchell, Gary F.
    Cardiovasc Engn Inc, Norwood, MA USA..
    Smith, Nicholas L.
    Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.;Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA.;Seattle Epidemiol Res & Informat Ctr, Dept Vet Affairs Off Res & Dev, Seattle, WA USA..
    Fox, Ervin R.
    Univ Mississippi, Med Ctr, Div Cardiol, Jackson, MS 39216 USA..
    Dueker, Nicole D.
    Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL USA..
    Jaddoe, Vincent W. V.
    Univ Med Ctr Rotterdam, Dept Epidemiol, Erasmus MC, Rotterdam, Netherlands.;Generat R Study Grp, Rotterdam, Netherlands.;Univ Med Ctr Rotterdam, Dept Pediat, Erasmus MC, Rotterdam, Netherlands..
    Melander, Olle
    Lund Univ, Dept Clin Sci, Malmo, Sweden.;Skane Univ Hosp, Dept Internal Med, Malmo, Sweden..
    Russ, Martin
    Univ Clin Halle Saale, Martin Luther Univ Halle Wittenberg, Dept Med 3, Halle, Germany.;Helios Amperklin Dachau, Dachau, Germany..
    Lehtimaki, Terho
    Dept Clin Chem, Fimlab Labs, Tampere, Finland.;Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Tampere, Finland..
    Ciullo, Marina
    Inst Genet & Biophys A Buzzati Traverso, CNR, Naples, Italy.;IRCCS Neuromed, Pozzilli, Isernia, Italy..
    Hicks, Andrew A.
    Univ Lubeck, European Acad Bolzano Bozen, Ctr Biomed, Lubeck, Germany.;Univ Lubeck, Affiliated Inst, Lubeck, Germany..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Gudnason, Vilmundur
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Pieske, Burkert
    Med Univ Graz, Dept Cariol, Graz, Austria.;Charite Univ Med Berlin, Dept Cardiol, Campus Virchow Klinikum, Berlin, Germany.;German Heart Inst Berlin DHZB, Dept Internal Med Cardiol, Berlin, Germany..
    Barron, Anthony J.
    Hammersmith Hosp, Int Ctr Circulatory Hlth, London, England.;NHLI, Imperial Coll London, London, England..
    Zweiker, Robert
    Med Univ Graz, Dept Cariol, Graz, Austria..
    Schunkert, Heribert
    DZHK Partner Site Munich Heart Alliance, Munich, Germany.;Tech Univ Munich, Deutsches Herzzentrum, Munich, Germany..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Liu, Kiang
    Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA..
    Arnett, Donna K.
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA..
    Psaty, Bruce M.
    Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA.;Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Epidemiol & Hlth Serv, Seattle, WA 98195 USA..
    Blankenberg, Stefan
    DZHK Partner Site Hamburg Kiel Lubeck, Hamburg, Germany.;Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, Hamburg, Germany..
    Larson, Martin G.
    Boston Univ, Sch Publ Hlth, Biostat Dept, Boston, MA 02215 USA.;Boston Univ, Dept Math & Stat, Boston, MA USA..
    Felix, Stephan B.
    DZHK Partner Site Greifswald, Greifswald, Germany.;Univ Med Greifswald, Dept Internal Med B, Ferdinand Sauerbruch Str, D-17475 Greifswald, Germany..
    Franco, Oscar H.
    Univ Med Ctr Rotterdam, Dept Epidemiol, Erasmus MC, Rotterdam, Netherlands..
    Zeller, Tanja
    DZHK Partner Site Hamburg Kiel Lubeck, Hamburg, Germany.;Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, Hamburg, Germany..
    Vasan, Ramachandran S.
    Natl Heart Lung & Blood Inst, Framingham, MA USA.;Boston Univ Framingham Heart Study, Framingham, MA USA.;Boston Univ, Sch Med & Publ Hlth, Sect Cardiol, Prevent Med & Epidemiol, Boston, MA USA.;Boston Univ, Sch Med & Framingham Heart Study, Dept Med, Sect Prevent Med & Epidemiol & Cardiol, 801 Massachusetts Ave,Suite 470, Boston, MA 02118 USA..
    Doerr, Marcus
    DZHK Partner Site Greifswald, Greifswald, Germany.;Univ Med Greifswald, Dept Internal Med B, Ferdinand Sauerbruch Str, D-17475 Greifswald, Germany..
    Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function2017In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 127, no 5, p. 1798-1812Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS. A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS. The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION. The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.

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