1. Epicardial perivascular adipose-derived leptin exacerbates coronary endothelial dysfunction in metabolic syndrome via a protein kinase C-beta pathway.
- Author
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Payne GA, Borbouse L, Kumar S, Neeb Z, Alloosh M, Sturek M, and Tune JD
- Subjects
- Animals, Coronary Vessels drug effects, Coronary Vessels physiopathology, Disease Models, Animal, Dose-Response Relationship, Drug, Endothelium, Vascular drug effects, Endothelium, Vascular physiopathology, Female, Male, Metabolic Syndrome physiopathology, Pericardium, Phenotype, Protein Kinase C antagonists & inhibitors, Protein Kinase C beta, Protein Kinase Inhibitors pharmacology, Receptors, Leptin metabolism, Swine, Swine, Miniature, Up-Regulation, Vasodilator Agents pharmacology, Adipose Tissue metabolism, Coronary Vessels enzymology, Endothelium, Vascular enzymology, Leptin metabolism, Metabolic Syndrome enzymology, Protein Kinase C metabolism, Signal Transduction drug effects, Vasodilation drug effects
- Abstract
Objective: Factors released by perivascular adipose tissue (PVAT) disrupt coronary endothelial function via phosphorylation of endothelial NO synthase by protein kinase C (PKC)-beta. 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-beta 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-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 PKC-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 PKC-beta-dependent pathway. These findings implicate PVAT-derived leptin as a potential contributor to coronary atherogenesis in MetS.
- Published
- 2010
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