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Protection Against Myocardial Infarction and No-Reflow Through Preservation of Vascular Integrity by Angiopoietin-Like 4
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2012 (English)In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 125, no 1, 140-149 p.Article in journal (Refereed) Published
Abstract [en]

Background-Increased permeability, predominantly controlled by endothelial junction stability, is an early event in the deterioration of vascular integrity in ischemic disorders. Hemorrhage, edema, and inflammation are the main features of reperfusion injuries, as observed in acute myocardial infarction (AMI). Thus, preservation of vascular integrity is fundamental in ischemic heart disease. Angiopoietins are pivotal modulators of cell-cell junctions and vascular integrity. We hypothesized that hypoxic induction of angiopoietin-like protein 4 (ANGPTL4) might modulate vascular damage, infarct size, and no-reflow during AMI. Methods and Results-We showed that vascular permeability, hemorrhage, edema, inflammation, and infarct severity were increased in angptl4-deficient mice. We determined that decrease in vascular endothelial growth factor receptor 2 (VEGFR2) and VE-cadherin expression and increase in Src kinase phosphorylation downstream of VEGFR2 were accentuated after ischemia-reperfusion in the coronary microcirculation of angptl4-deficient mice. Both events led to altered VEGFR2/VE-cadherin complexes and to disrupted adherens junctions in the endothelial cells of angptl4-deficient mice that correlated with increased no-reflow. In vivo injection of recombinant human ANGPTL4 protected VEGF-driven dissociation of the VEGFR2/VE-cadherin complex, reduced myocardial infarct size, and the extent of no-reflow in mice and rabbits. Conclusions-These data showed that ANGPTL4 might constitute a relevant target for therapeutic vasculoprotection aimed at counteracting the effects of VEGF, thus being crucial for preventing no-reflow and conferring secondary cardioprotection during AMI.

Place, publisher, year, edition, pages
2012. Vol. 125, no 1, 140-149 p.
Keyword [en]
no-reflow, acute myocardial infarction, endothelial cells, vascular integrity, hypoxia
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-168593DOI: 10.1161/CIRCULATIONAHA.111.049072ISI: 000299169100027OAI: oai:DiVA.org:uu-168593DiVA: diva2:501534
Available from: 2012-02-14 Created: 2012-02-13 Last updated: 2017-12-07Bibliographically approved

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Department of Medical Biochemistry and Microbiology
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