Abstract 16972: Oxidation Products From the Human Heart Trigger PPAR-γ Signalling in Epicardial Fat and Stimulate the Release of Adiponectin: a Novel Role of Epicardial Fat in the Regulation of Myocardial Redox State

Introduction: Adiponectin (AdN) has antioxidant effects in experimental models, but its impact on human myocardial redox state is unknown. We hypothesised the existence of a cross-talk between epicardial adipose tissue (EpAT) and the myocardium and examined the role of AdN released from human EpAT in the regulation of myocardial redox state. Methods: We recruited 251 pts undergoing CABG. EpAT and right atrium appendages (RAA) were collected. O2- was measured in RAA by chemiluminescence. In 34 additional patients, RAA were incubated with AdN (10ug/mL) ±AMPK inhibitor compound-C for 2h, while to explore the signalling from the heart to the EpAT, human EpAT was co-cultured with H9C2 cardiomyocytes ± NADPH (to trigger O2- production by NADPH-oxidase) or exposed to oxidation products 4-hydroxynonenal (4HNE) or malonyldialdehyde (MDA) for 16h, and ADIPOQ expression was quantified. By using rapid atrial pacing for 6 weeks as a means to increase O2- production in the left atrium of a pig model, we also quantified ADIPOQ expression in pig EpAT. Results: NADPH oxidase activity in human RAA is positively correlated with circulating AdN and ADIPOQ expression in EpAT (A). AdN suppressed myocardial NADPH oxidase activity ex-vivo (B) by inhibiting membrane translocation of Rac1 in an AMPK-dependent manner (C). ADIPOQ expression was increased in the EpAT co-cultured with NADPH-treated H9c2 cells (D) or exposed to 4HNE (but not MDA) in a PPAR-y-dependent manner (reversed by T0070907) (E). LA pacing in the pig model increased myocardial NADPH-oxidase activity and triggered ADIPOQ expression in EpAT (F). Conclusions: Increased myocardial NADPH oxidase activity up-regulates ADIPOQ expression in EpAT, serving as a local mechanism to counteract myocardial oxidative stress. These novel findings introduce the concept of a crosstalk between EpAT and myocardial redox state, with 4HNE and AdN acting as messengers between the two.