TGR5 activation induces cytoprotective changes in the heart and improves myocardial adaptability to physiologic, inotropic, and pressure-induced stress in mice

IntroductionAdministration of cholic acid, or its synthetic derivative, 6-alpha-ethyl-23(S)-methylcholic acid (INT-777), activates the membrane GPCR, TGR5, influences whole body metabolism, reduces atherosclerosis, and benefits the cardiovascular physiology in mice. Direct effects of TGR5 agonists, and the role for TGR5, on myocardial cell biology and stress response are unknown. MethodsMice were fed chow supplemented with 0.5% cholic acid (CA) or 0.025% INT-777, a specific TGR5 agonist, or regular chow for 3weeks. Anthropometric, biochemical, physiologic (electrocardiography and echocardiography), and molecular analysis was performed at baseline. CA and INT-777 fed mice were challenged with acute exercise-induced stress, acute catecholamine-induced stress, and hemodynamic stress induced by transverse aortic constriction (TAC) for a period of 8weeks. In separate experiments, mice born with constitutive deletion of TGR5 in cardiomyocytes (CM-TGR5(del)) were exposed to exercise, inotropic, and TAC-induced stress. ResultsAdministration of CA and INT-777 supplemented diets upregulated TGR5 expression and activated Akt, PKA, and ERK1/2 in the heart. CA and INT-777 fed mice showed improved exercise tolerance, improved sensitivity to catecholamine and attenuation in pathologic remodeling of the heart under hemodynamic stress. In contrast, CM-TGR5(del) showed poor response to exercise and catecholamine challenge as well as higher mortality and signs of accelerated cardiomyopathy under hemodynamic stress. ConclusionsBile acids, specifically TGR5 agonists, induce cytoprotective changes in the heart and improve myocardial response to physiologic, inotropic, and hemodynamic stress in mice. TGR5 plays a critical role in myocardial adaptability, and TGR5 activation may represent a potentially attractive treatment option in heart failure.