Adiponectin Determines Farnesoid X Receptor Agonism-Mediated Cardioprotection Against Post-Infarction Remodeling and Dysfunction

ptor superfamily that plays a critical regulatory role in cardiovascular physiology/pathology. However, the role of systemic FXR activation in the chronic phase in myocardial infarction (MI)-induced cardiac remodeling and dysfunction remains unclear. In this study, we aimed to elucidate the role of long-term FXR activation on post-MI cardiac remodeling and dysfunction. Methods and Results: Mice underwent either MI surgery or sham operation. At 1 week after MI, both sham and MI mice were gavaged with 25mg/kg/d of a synthetic FXR agonist (GW4064) or a vehicle control for 7 weeks, and cardiac performance was assessed by consecutive echocardiography studies. Administration of GW4064 significantly increased left ventricular ejection fraction at 4 weeks and 8 weeks after MI (both P<0.01). Moreover, GW4064 treatment increased angiogenesis and mitochondrial biogenesis, reduced cardiomyocyte loss and inflammation, and ameliorated cardiac remodeling as evidenced by heart weight, lung weight, atrial natriuretic peptide (ANP)/brain natriuretic peptide (BNP) levels, and myocardial fibrosis at 8 weeks post-MI. At the molecular level, GW4064 significantly increased FXR mRNA expression and transcriptional activity in heart tissue. Moreover, overexpression of myocardial FXR failed to exert significant cardioprotection in vivo, indicating that GW4064 improved post-MI heart remodeling and function independent of myocardial FXR expression/activity. Among the 4 downstream soluble molecules of FXR, plasma adiponectin was most significantly increased by GW4064. In cultured adipocytes, GW4064 increased mRNA levels and protein expression of adiponectin. Conditioned medium of GW4064-treated adipocytes activated AMPK-PGC-1α signaling and reduced hypoxia-induced cardiomyocyte apoptosis, all of which were attenuated by an adiponectin neutralizing antibody. More importantly, when knocking-out adiponectin in mice, the cardioprotective effects of GW4064 were attenuated. Conclusions: We are the first to show that FXR agonism ameliorated post-MI cardiac dysfunction and remodeling by stimulating adiponectin secretion. Thus, we demonstrated that FXR agonism is a potential therapeutic strategy in post-MI heart failure.