Novel PGC-1 α/ATF5 Axis Partly Activates UPRmt and Mediates Cardioprotective Role of Tetrahydrocurcumin in Pathological Cardiac Hypertrophy

Abstract

Mitochondrial unfolding protein response (UPR^mt) effectively resists the pathological cardiac hypertrophy and improves the mitochondrial function. However, the specific activation mechanism and drugs that can effectively activate UPR^mt in the cardiac muscle are yet to be elucidated. The aim of this study was to determine the regulation role of UPR^mt on preventing pathological cardiac hypertrophy by tetrahydrocurcumin (THC) and explore its underlying molecular mechanism. Male C57BL/6J wild-type (WT) mice were divided into a control group and subjected to sham treatment for 4 weeks, and a test group which was subjected to transverse aortic constriction (TAC) surgery. Animals in the control and test group were orally administered THC (50 mg/kg) for 4 weeks after TAC procedure; an equivalent amount of saline was orally administered in the control sham-treated group and the TAC group. Subsequently, oxidative stress and UPR^mt markers were assessed in these mice, and cardiac hypertrophy, fibrosis, and cardiac function were tested. Small interfering RNA (siRNA) targeting proliferator-activated receptor-gamma coactivator (PGC)-1α and activating transcription factor 5 (ATF5) were used to determine the UPR^mt activation mechanism. THC supplement partly upregulated UPR^mt effectors and inhibited TAC-induced oxidative stress compared with TAC-operated WT mice, thereby substantially attenuating contractile dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, PGC-1α knockdown blunted the UPR^mt activation and the cardioprotective role of THC. The interaction between PGC-1α and ATF5 was tested in neonatal rat cardiac myocytes under normal conditions. The results showed that PGC-1α was an upstream effector of ATF5 and partly activated UPR^mt. In vitro, phenylephrine- (PE-) induced cardiomyocyte hypertrophy caused ATF5 upregulating rather than downregulating corresponding to the downregulation of PGC-1α. The PGC-1α/ATF5 axis mediated the UPR^mt activation and stress-resistance role of THC in vitro. Collectively, the present study provides the first evidence that PGC-1 and ATF5 can form a signaling axis to partly activate UPR^mt that mediates the cardioprotective role of THC in pathological cardiac hypertrophy.