Lefranc 2019 Hypertension
|Lefranc C, Friederich-Persson M, Braud L, Palacios-Ramirez R, Karlsson S, Boujardine N, Motterlini R, Jaisser F, Nguyen Dinh Cat A (2019) MR (mineralocorticoid receptor) induces adipose tissue senescence and mitochondrial dysfunction leading to vascular dysfunction in obesity. Hypertension 73:458-68.|
Abstract: 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.
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Aging;senescence, Obesity
Organism: Mouse Tissue;cell: Fat Preparation: Isolated mitochondria
Coupling state: LEAK, OXPHOS Pathway: N HRR: Oxygraph-2k, O2k-Fluorometer