Epicardial perivascular adipose-derived leptin exacerbates coronary endothelial dysfunction in metabolic syndrome via a protein kinase C-beta pathway.

OBJECTIVE:Factors released by perivascular adipose tissue (PVAT) disrupt coronary endothelial function via phosphorylation of endothelial NO synthase by protein kinase C However, our understanding of how PVAT potentially contributes to coronary disease as a complication of obesity/metabolic syndrome (MetS) remains limited. The current study investigated whether PVAT-derived leptin impairs coronary vascular function via in MetS. METHODS AND RESULTS:Coronary arteries with and without PVAT were collected from lean or MetS Ossabaw miniature swine for isometric tension studies. Endothelial-dependent vasodilation to bradykinin was significantly reduced in MetS. PVAT did not affect bradykinin-mediated dilation in arteries from lean swine but significantly exacerbated endothelial dysfunction in arteries from MetS swine. PVAT-induced impairment was reversed by inhibition of either duanyu1531-beta with ruboxistaurin (Eli Lilly and Company, Indianapolis, Ind) or leptin receptor signaling with a recombinant, pegylated leptin antagonist. Western blot and immunohistochemical analyses demonstrated increased PVAT-derived leptin and coronary leptin receptor density with MetS. Coronary duanyu1531-beta activity was increased in both MetS arteries exposed to PVAT and lean arteries exposed to leptin. Finally, leptin-induced endothelial dysfunction was reversed by ruboxistaurin. CONCLUSIONS:Increases in epicardial PVAT leptin exacerbate coronary endothelial dysfunction in MetS via a pathway. These findings implicate PVAT-derived leptin as a potential contributor to coronary atherogenesis in MetS.

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