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

Gregory A. Payne, Léna Borbouse, Sajel Kumar, Zachary Neeb, Mouhamad Alloosh, Michael Sturek, Johnathan D. Tune

Research output: Contribution to journalArticle

126 Scopus citations

Abstract

Objective: Factors released by perivascular adipose tissue (PVAT) disrupt coronary endothelial function via phosphorylation of endothelial NO synthase by protein kinase C (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 (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 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)1711-1717
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume30
Issue number9
DOIs
StatePublished - Sep 1 2010

Keywords

  • coronary artery disease
  • endothelium
  • epicardial perivascular adipose tissue
  • obesity

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

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