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

doi:10.1161/CIRCRESAHA.115.307856

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

Circ Res. 2016 Mar 4;118(5):842-55. doi: 10.1161/CIRCRESAHA.115.307856. Epub 2016 Jan 21.

Authors

Alexios S Antonopoulos¹, Marios Margaritis¹, Sander Verheule¹, Alice Recalde¹, Fabio Sanna¹, Laura Herdman¹, Costas Psarros¹, Hussein Nasrallah¹, Patricia Coutinho¹, Ioannis Akoumianakis¹, Alison C Brewer¹, Rana Sayeed¹, George Krasopoulos¹, Mario Petrou¹, Akansha Tarun¹, Dimitris Tousoulis¹, Ajay M Shah¹, Barbara Casadei¹, Keith M Channon¹, Charalambos Antoniades²

Affiliations

¹ From the Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom (A.S.A., M.M., A.R., F.S., L.H., C.P., P.C., I.A., A.T., B.C., K.M.C., C.A.); Cardiac Electrophysiology Group, Department of Physiology, Maastricht University, Maastricht, The Netherlands (S.V., H.N.); Department of Cardiology, Athens University Medical School, Athens, Greece (D.T.); Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (A.C.B., A.M.S.); and Department of Cardiac Surgery, John Radcliffe Hospital, Oxford, United Kingdom (R.S., G.K., M.P.).
² From the Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom (A.S.A., M.M., A.R., F.S., L.H., C.P., P.C., I.A., A.T., B.C., K.M.C., C.A.); Cardiac Electrophysiology Group, Department of Physiology, Maastricht University, Maastricht, The Netherlands (S.V., H.N.); Department of Cardiology, Athens University Medical School, Athens, Greece (D.T.); Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (A.C.B., A.M.S.); and Department of Cardiac Surgery, John Radcliffe Hospital, Oxford, United Kingdom (R.S., G.K., M.P.). antoniad@well.ox.ac.uk.

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.

Keywords: adiponectin; adipose tissue; myocardium; obesity; oxidative stress.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adiponectin / biosynthesis*
Adipose Tissue / cytology
Adipose Tissue / metabolism*
Animals
Cell Line
Female
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Myocardium / cytology
Myocardium / metabolism*
Organ Culture Techniques
Oxidation-Reduction
PPAR gamma / biosynthesis*
Pericardium / cytology
Pericardium / metabolism*
Rats
Swine

Substances

ADIPOQ protein, human
Adiponectin
PPAR gamma

Abstract

Publication types

MeSH terms

Substances

Grants and funding