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

Alexios S. Antonopoulos, Marios Margaritis, Sander Verheule, Alice Recalde, Fabio Sanna, Laura Herdman, Costas Psarros, Hussein Nasrallah, Patricia Coutinho, Ioannis Akoumianakis, Alison C. Brewer, Rana Sayeed, George Krasopoulos, Mario Petrou, Akansha Tarun, Dimitris Tousoulis, Ajay M. Shah, Barbara Casadei, Keith M. Channon, Charalambos Antoniades*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

94 Citations (Web of Science)

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 O-2(-), whereas circulating adiponectin and ADIPOQ expression in EpAT were associated with elevated myocardial O-2(-). 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 O-2(-) production in H9C2 cardiac myocytes led to the release of a transferable factor able to induce peroxisome proliferator-activated receptor-gamma-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-gamma-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.
Original languageEnglish
Pages (from-to)842-855
JournalCirculation Research
Volume118
Issue number5
DOIs
Publication statusPublished - 4 Mar 2016

Keywords

  • obesity
  • adipose tissue
  • adiponectin
  • oxidative stress
  • myocardium

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