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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)-1 α  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-1 α  knockdown blunted the UPR mt  activation and the cardioprotective role of THC. The interaction between PGC-1 α  and ATF5 was tested in neonatal rat cardiac myocytes under normal conditions. The results showed that PGC-1 α  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-1 α . The PGC-1 α /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.

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