Mutual Regulation of Epicardial Adipose Tissue and Myocardial Redox State by PPAR-γ/Adiponectin Signalling

Abstract

RATIONALE Adiponectin has anti-inflammatory effects in experimental models, but its role in the regulation of myocardial redox state in humans is unknown. Although adiponectin is released from epicardial adipose tissue (EpAT), it is unclear whether it exerts any paracrine effects on the human myocardium. OBJECTIVE To explore the cross talk between EpAT-derived adiponectin and myocardial redox state in the human heart. METHODS AND RESULTS EpAT and atrial myocardium were obtained from 306 patients undergoing coronary artery bypass grafting. Functional genetic polymorphisms that increase ADIPOQ expression (encoding adiponectin) led to reduced myocardial nicotinamide adenine dinucleotide phosphate oxidase-derived O2 (-), whereas circulating adiponectin and ADIPOQ expression in EpAT were associated with elevated myocardial O2 (-). In human atrial tissue, we demonstrated that adiponectin suppresses myocardial nicotinamide adenine dinucleotide phosphate oxidase activity, by preventing AMP kinase-mediated translocation of Rac1 and p47(phox) from the cytosol to the membranes. Induction of O2 (-) production in H9C2 cardiac myocytes led to the release of a transferable factor able to induce peroxisome proliferator-activated receptor-γ-mediated upregulation of ADIPOQ expression in cocultured EpAT. Using a NOX2 transgenic mouse and a pig model of rapid atrial pacing, we found that oxidation products (such as 4-hydroxynonenal) released from the heart trigger peroxisome proliferator-activated receptor-γ-mediated upregulation of ADIPOQ in EpAT. CONCLUSIONS We demonstrate for the first time in humans that adiponectin directly decreases myocardial nicotinamide adenine dinucleotide phosphate oxidase activity via endocrine or paracrine effects. Adiponectin expression in EpAT is controlled by paracrine effects of oxidation products released from the heart. These effects constitute a novel defense mechanism of the heart against myocardial oxidative stress.

DOI: 10.1161/CIRCRESAHA.115.307856

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@inproceedings{Antonopoulos2016MutualRO, title={Mutual Regulation of Epicardial Adipose Tissue and Myocardial Redox State by PPAR-γ/Adiponectin Signalling}, author={Alexios S Antonopoulos and Marios Margaritis and Sander Verheule and Alice Recalde and Fabio Sanna and Laura Herdman and Costas T. Psarros and Hussein M Nasrallah and Patricia Coutinho and Ioannis Akoumianakis and Alison C. Brewer and Rana Sayeed and George Krasopoulos and Mario Petrou and Akansha Tarun and Dimitris Tousoulis and Ajay Shah and Barbara Casadei and Keith M. Channon and Charalambos Antoniades}, booktitle={Circulation research}, year={2016} }