TGF-β improves myocardial function and prevents apoptosis induced by anoxia-reoxygenation, through the reduction of endoplasmic reticulum stress

Background: Transforming growth factor-beta (TGF-beta) is known for its role in ventricular remodeling, inflammatory response, cell survival, and apoptosis. However, its role in improving myocardial function in rat hearts subjected to ischemia-reperfusion (I/R) and protecting against apoptosis induced in cardiomyocytes by anoxia-reoxygenation (A/R) has not been elucidated. This study investigated the protective effects and molecular mechanisms of TGF-beta on myocardial function and cardiomyocyte apoptosis. Methods and results: We used TUNEL staining, we tested cell viability, and we measured mitochondrial membrane potential and levels of mitochondrial ROS after 6 h of simulated anoxia together with various durations of simulated reoxygenation in H9c2 cells. We further observed the contractile function in rat hearts after they were subjected to 30 min global ischemia and 180 min reperfusion. Pretreatment with TGF-beta markedly inhibited apoptosis in H9c2 cells, as evidenced by increased cell viability and decreased numbers of TUNEL-positive cells, maintained mitochondrial membrane potential, and diminished mitochondrial production of reactive oxygen species (ROS). These changes were associated with the inhibition of endoplasmic reticulum (ER) stress-dependent markers of apoptosis (GRP78, CHOP, caspase-12, and JNK), and the modulation of the expression of Bcl2/Bax. Furthermore, TGF-beta improved I/R-induced myocardial contractile dysfunction. All of these protective effects were concentration-dependent. Conclusion: Our results show that TGF-beta prevents A/R-induced apoptosis of cardiomyocytes and improves myocardial function in rat hearts injured by I/R.