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MR (Mineralocorticoid Receptor) Induces Adipose Tissue Senescence and Mitochondrial Dysfunction Leading to Vascular Dysfunction in Obesity
Sorbonne Univ, Ctr Rech Cordeliers, INSERM, Dept Physiol,UMRS 1138,Team 1, Paris, France.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Univ Paris Est Creteil, INSERM, Dept Pathophysiol Cardiovasc & Resp Dis, Dev & Senescence,U955,Team 12, Creteil, France.
Sorbonne Univ, Ctr Rech Cordeliers, INSERM, Dept Physiol,UMRS 1138,Team 1, Paris, France.ORCID iD: 0000-0002-0867-1277
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2019 (English)In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 73, no 2, p. 458-468Article in journal (Refereed) Published
Abstract [en]

Adipose tissue (AT) senescence and mitochondrial dysfunction are associated with obesity. Studies in obese patients and animals demonstrate that the MR (mineralocorticoid receptor) contributes to obesity-associated cardiovascular complications through its specific role in AT. However, underlying mechanisms remain unclear. This study aims to elucidate whether MR regulates mitochondrial function in obesity, resulting in AT premature aging and vascular dysfunction. Obese (db/db) and lean (db/+) mice were treated with an MR antagonist or a specific mitochondria-targeted antioxidant. Mitochondrial and vascular functions were determined by respirometry and myography, respectively. Molecular mechanisms were probed by Western immunoblotting and real-time polymerase chain reaction in visceral AT and arteries and focused on senescence markers and redox-sensitive pathways. db/db mice displayed AT senescence with activation of the p53-p21 pathway and decreased SIRT (sirtuin) levels, as well as mitochondrial dysfunction. Furthermore, the beneficial anticontractile effects of perivascular AT were lost in db/db via ROCK (Rho kinase) activation. MR blockade prevented these effects. Thus, MR activation in obesity induces mitochondrial dysfunction and AT senescence and dysfunction, which consequently increases vascular contractility. In conclusion, our study identifies novel mechanistic insights involving MR, adipose mitochondria, and vascular function that may be of importance to develop new therapeutic strategies to limit obesity-associated cardiovascular complications.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS , 2019. Vol. 73, no 2, p. 458-468
Keywords [en]
adipose tissue, aging, mitochondria, obesity, oxidative stress, sirtuins, vasoconstriction
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:uu:diva-381200DOI: 10.1161/HYPERTENSIONAHA.118.11873ISI: 000461318900033PubMedID: 30624990OAI: oai:DiVA.org:uu-381200DiVA, id: diva2:1303728
Funder
Wenner-Gren FoundationsMagnus Bergvall FoundationÅke Wiberg FoundationAvailable from: 2019-04-10 Created: 2019-04-10 Last updated: 2019-04-10Bibliographically approved

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Friederich, MalouKarlsson, Susanne

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