Objective Factors released by perivascular adipose tissue (PVAT) disrupt coronary endothelial function via phosphorylation of eNOS by PKC-β. 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 PKC-β 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 PKC-β with ruboxistaurin or leptin receptor signaling with a recombinant, pegylated leptin antagonist. Western and immunohistochemical analysis demonstrated increased PVAT-derived leptin and coronary leptin receptor (ObR) density with MetS. Coronary PKC-β 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 PKC-β-dependent pathway. These findings implicate PVAT-derived leptin as a potential contributor to coronary atherogenesis in MetS.

This study tested the hypothesis that augmented release of leptin from epicardial perivascular adipose tissue (PVAT) exacerbates coronary endothelial dysfunction in metabolic syndrome (MetS) via a PKC‐β pathway. Coronary arteries with and without PVAT were collected from lean or MetS Ossabaw swine. Isometric tension studies demonstrated endothelial‐dependent vasodilation to bradykinin was reduced by MetS alone. PVAT did not affect vascular function in lean arteries, but exacerbated endothelial dysfunction by 28% in MetS arteries. This effect of PVAT was significantly attenuated by inhibition of either PKC‐β with ruboxistaurin (1 μM) or leptin receptor (ObRb) signaling with a recombinant, pegylated leptin antagonist (1 μM). Western analyses revealed a 50% increase in leptin expression in MetS PVAT, and a 20% increase in MetS coronary ObRb density. Immunohistochemistry confirmed ObRb expression in coronary endothelium. Leptin alone (30 ng/ml) diminished endothelial‐dependent dilation in lean arteries without PVAT and increased PKC activity > 3‐fold. PKC activity was also increased ~ 3‐fold in coronary arteries from MetS vs. lean swine. These effects were reversed by pre‐treatment with ruboxistaurin (1 μM). In conclusion, increased epicardial PVAT leptin expression exacerbates coronary endothelial dysfunction in MetS primarily via a PKC‐β‐dependent pathway. (Support: HL092245; HL62552; RR13233)