Epicardial perivascular adipose tissue exacerbates coronary endothelial dysfunction in metabolic syndrome via leptin‐induced activation of PKC‐β

Abstract

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)