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Endothelial PGC-1? mediates vascular dysfunction in diabetes.

ABSTRACT: Endothelial dysfunction is a central hallmark of diabetes. The transcriptional coactivator PGC-1? is a powerful regulator of metabolism, but its role in endothelial cells remains poorly understood. We show here that endothelial PGC-1? expression is high in diabetic rodents and humans and that PGC-1? powerfully blocks endothelial migration in cell culture and vasculogenesis in vivo. Mechanistically, PGC-1? induces Notch signaling, blunts activation of Rac/Akt/eNOS signaling, and renders endothelial cells unresponsive to established angiogenic factors. Transgenic overexpression of PGC-1? in the endothelium mimics multiple diabetic phenotypes, including aberrant re-endothelialization after carotid injury, blunted wound healing, and reduced blood flow recovery after hindlimb ischemia. Conversely, deletion of endothelial PGC-1? rescues the blunted wound healing and recovery from hindlimb ischemia seen in type 1 and type 2 diabetes. Endothelial PGC-1? thus potently inhibits endothelial function and angiogenesis, and induction of endothelial PGC-1? contributes to multiple aspects of vascular dysfunction in diabetes.

SUBMITTER: Sawada N

PROVIDER: S-EPMC4040246 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Endothelial PGC-1α mediates vascular dysfunction in diabetes.

Sawada Naoki N Jiang Aihua A Takizawa Fumihiko F Safdar Adeel A Manika Andre A Tesmenitsky Yevgenia Y Kang Kyu-Tae KT Bischoff Joyce J Kalwa Hermann H Sartoretto Juliano L JL Kamei Yasutomi Y Benjamin Laura E LE Watada Hirotaka H Ogawa Yoshihiro Y Higashikuni Yasutomi Y Kessinger Chase W CW Jaffer Farouc A FA Michel Thomas T Sata Masataka M Croce Kevin K Tanaka Rica R Arany Zolt Z

Cell metabolism 20140201 2

Endothelial dysfunction is a central hallmark of diabetes. The transcriptional coactivator PGC-1α is a powerful regulator of metabolism, but its role in endothelial cells remains poorly understood. We show here that endothelial PGC-1α expression is high in diabetic rodents and humans and that PGC-1α powerfully blocks endothelial migration in cell culture and vasculogenesis in vivo. Mechanistically, PGC-1α induces Notch signaling, blunts activation of Rac/Akt/eNOS signaling, and renders endotheli ...[more]

PMID: 24506866

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Project description:AimsAldosterone plays a crucial role in cardiovascular disease. 'Systemic' inhibition of its mineralocorticoid receptor (MR) decreases atherosclerosis by reducing inflammation and oxidative stress. Obesity, an important cardiovascular risk factor, is an inflammatory disease associated with increased plasma aldosterone levels. We have investigated the role of the 'endothelial' MR in obesity-induced endothelial dysfunction, the earliest stage in atherogenesis.Methods and resultsC57BL/6 mice were exposed to a normal chow diet (ND) or a high-fat diet (HFD) alone or in combination with the MR antagonist eplerenone (200 mg/kg/day) for 14 weeks. Diet-induced obesity impaired endothelium-dependent relaxation in response to acetylcholine, whereas eplerenone treatment of obese mice prevented this. Expression analyses in aortic endothelial cells isolated from these mice revealed that eplerenone attenuated expression of pro-oxidative NADPH oxidase (subunits p22phox, p40phox) and increased expression of antioxidative genes (glutathione peroxidase-1, superoxide dismutase-1 and -3) in obesity. Eplerenone did not affect obesity-induced upregulation of cyclooxygenase (COX)-1 or prostacyclin synthase. Endothelial-specific MR deletion prevented endothelial dysfunction in obese (exhibiting high 'endogenous' aldosterone) and in 'exogenous' aldosterone-infused lean mice. Pre-incubation of aortic rings from aldosterone-treated animals with the COX-inhibitor indomethacin restored endothelial function. Exogenous aldosterone administration induced endothelial expression of p22phox in the presence, but not in the absence of the endothelial MR.ConclusionObesity-induced endothelial dysfunction depends on the 'endothelial' MR and is mediated by an imbalance of oxidative stress-modulating mechanisms. Therefore, MR antagonists may represent an attractive therapeutic strategy in the increasing population of obese patients to decrease vascular dysfunction and subsequent atherosclerotic complications.

Dataset Information

Endothelial PGC-1? mediates vascular dysfunction in diabetes.

Publications

Endothelial PGC-1α mediates vascular dysfunction in diabetes.

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