TGR 5 activation induces cytoprotective changes in the heart and improves myocardial adaptability to physiologic, inotropic, and pressure‐induced stress in mice

Administration of cholic acid, or its synthetic derivative, 6‐alpha‐ethyl‐23(S)‐methylcholic acid ( INT ‐777), activates the membrane GPCR , TGR 5, influences whole body metabolism, reduces atherosclerosis, and benefits the cardiovascular physiology in mice. Direct effects of TGR 5 agonists, and the role for TGR 5, on myocardial cell biology and stress response are unknown. Methods Mice were fed chow supplemented with 0.5% cholic acid ( CA ) or 0.025% INT ‐777, a specific TGR 5 agonist, or regular chow for 3 weeks. 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 8 weeks. In separate experiments, mice born with constitutive deletion of TGR 5 in cardiomyocytes ( CM ‐ TGR 5 del ) were exposed to exercise, inotropic, and TAC ‐induced stress. Results Administration of CA and INT ‐777 supplemented diets upregulated TGR 5 expression and activated Akt, PKA , and ERK 1/2 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 ‐ TGR 5 del showed poor response to exercise and catecholamine challenge as well as higher mortality and signs of accelerated cardiomyopathy under hemodynamic stress. Conclusions Bile acids, specifically TGR 5 agonists, induce cytoprotective changes in the heart and improve myocardial response to physiologic, inotropic, and hemodynamic stress in mice. TGR 5 plays a critical role in myocardial adaptability, and TGR 5 activation may represent a potentially attractive treatment option in heart failure.