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 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.

Novel Contributors and Mechanisms of Cellular Senescence in Hypertension-Associated Premature Vascular Aging

“…Recently, it was observed that adipose tissue senescence, via mineralocorticoid receptor activation, contributed to increased arterial contractile responses. 74 This illustrates that senescent PVAT can mediate premature vascular aging by promoting hypercontractility.…”

Perivascular Adipose Tissue as a Target for Antioxidant Therapy for Cardiovascular Complications

“…Also, the deletion of PGC-1α (proliferator-activated receptor-gamma and coactivator 1 alpha) in aged PVASCs exacerbates arterial remodeling and attenuates the browning of adipose tissue [82]. A recent study has revealed that the mineralocorticoid receptor (MR) is activated in the mitochondria of PVAT in obese mice, which causes premature-aging in adipose tissue and senescence, resulting in the loss of the anticontractile effects [83]. These results suggest that downregulation of PGC-1α and mitochondrial dysfunction in PVAT may contribute to the aging phenotype.…”

The Role of Sirtuin1 in Regulating Endothelial Function, Arterial Remodeling and Vascular Aging

“…To date, few studies have investigated PVAT senescence, and both aging and obesity might affect PVAT in a comparable manner (Miao and Li, 2012). A recent report shows that mineralocorticoid receptor (MR) is activated in the mitochondria of PVAT which causes premature-aging in adipose tissue and senescence in obese mice model, resulting in the loss of PVAT anticontractile properties (Lefranc et al, 2019). This suggests that mitochondrial dysfunction in PVAT may contribute to the aging phenotype, which is worth further investigation.…”