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MR (Mineralocorticoid Receptor) Induces Adipose Tissue Senescence and Mitochondrial Dysfunction Leading to Vascular Dysfunction in Obesity

Abstract : Adipose tissue (AT) senescence and mitochondrial dysfunction are associated with obesity. Studies in obese patients and animals demonstrate that the mineralocorticoid receptor (MR) 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 PCR 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 sirtuins levels, as well as mitochondrial dysfunction. Furthermore, the beneficial anti-contractile effects of perivascular AT were lost in db/db via 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 obesityassociated cardiovascular complications.
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https://www.hal.inserm.fr/inserm-03217214
Contributor : Roberto Motterlini <>
Submitted on : Tuesday, May 4, 2021 - 4:46:15 PM
Last modification on : Friday, July 9, 2021 - 12:10:03 PM

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Clara Lefranc, Malou Friederich-Persson, Laura Braud, Roberto Palacios-Ramirez, Susanne Karlsson, et al.. MR (Mineralocorticoid Receptor) Induces Adipose Tissue Senescence and Mitochondrial Dysfunction Leading to Vascular Dysfunction in Obesity. Hypertension, American Heart Association, 2019, 73 (2), pp.458-468. ⟨10.1161/HYPERTENSIONAHA.118.11873⟩. ⟨inserm-03217214⟩

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