title: Mutual Regulation of Epicardial Adipose Tissue and Myocardial Redox State by PPAR-γ/Adiponectin Signalling.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Alexios S
authors.initials: AS
authors.lastname: Antonopoulos
authors.affiliation: 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.).
authors.forename: Marios
authors.initials: M
authors.lastname: Margaritis
authors.affiliation: 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.).
authors.forename: Sander
authors.initials: S
authors.lastname: Verheule
authors.affiliation: 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.).
authors.forename: Alice
authors.initials: A
authors.lastname: Recalde
authors.affiliation: 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.).
authors.forename: Fabio
authors.initials: F
authors.lastname: Sanna
authors.affiliation: 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.).
authors.forename: Laura
authors.initials: L
authors.lastname: Herdman
authors.affiliation: 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.).
authors.forename: Costas
authors.initials: C
authors.lastname: Psarros
authors.affiliation: 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.).
authors.forename: Hussein
authors.initials: H
authors.lastname: Nasrallah
authors.affiliation: 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.).
authors.forename: Patricia
authors.initials: P
authors.lastname: Coutinho
authors.affiliation: 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.).
authors.forename: Ioannis
authors.initials: I
authors.lastname: Akoumianakis
authors.affiliation: 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.).
authors.forename: Alison C
authors.initials: AC
authors.lastname: Brewer
authors.affiliation: 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.).
authors.forename: Rana
authors.initials: R
authors.lastname: Sayeed
authors.affiliation: 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.).
authors.forename: George
authors.initials: G
authors.lastname: Krasopoulos
authors.affiliation: 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.).
authors.forename: Mario
authors.initials: M
authors.lastname: Petrou
authors.affiliation: 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.).
authors.forename: Akansha
authors.initials: A
authors.lastname: Tarun
authors.affiliation: 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.).
authors.forename: Dimitris
authors.initials: D
authors.lastname: Tousoulis
authors.affiliation: 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.).
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
authors.affiliation: 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.).
authors.forename: Barbara
authors.initials: B
authors.lastname: Casadei
authors.affiliation: 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.).
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
authors.affiliation: 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.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Antoniades
mesh_terms: D052242:Adiponectin / Q000096:biosynthesis*; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009924:Organ Culture Techniques; D010084:Oxidation-Reduction; D047495:PPAR gamma / Q000096:biosynthesis*; D010496:Pericardium / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D013552:Swine
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; D047495:PPAR gamma
keywords: adiponectin; adipose tissue; myocardium; obesity; oxidative stress
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