Article Publish Status: FREE
Abstract Title:

Novel PGC-1/ATF5 Axis Partly Activates UPRand Mediates Cardioprotective Role of Tetrahydrocurcumin in Pathological Cardiac Hypertrophy.

Abstract Source:

Oxid Med Cell Longev. 2020 ;2020:9187065. Epub 2020 Dec 26. PMID: 33425220

Abstract Author(s):

Bing Zhang, Yanzhen Tan, Zhengbin Zhang, Pan Feng, Wenyuan Ding, Qian Wang, Hongliang Liang, Weixun Duan, Xiaowu Wang, Shiqiang Yu, Jincheng Liu, Dinghua Yi, Yang Sun, Wei Yi

Article Affiliation:

Bing Zhang


Mitochondrial unfolding protein response (UPR) effectively resists the pathological cardiac hypertrophy and improves the mitochondrial function. However, the specific activation mechanism and drugs that can effectively activate UPRin the cardiac muscle are yet to be elucidated. The aim of this study was to determine the regulation role of UPRon 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 UPRmarkers 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)-1and activating transcription factor 5 (ATF5) were used to determine the UPRactivation mechanism. THC supplement partly upregulated UPReffectors and inhibited TAC-induced oxidative stress compared with TAC-operated WT mice, thereby substantially attenuating contractile dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, PGC-1knockdown blunted the UPRactivation and the cardioprotective role of THC. The interaction between PGC-1and ATF5 was tested in neonatal rat cardiac myocytes under normal conditions. The results showed that PGC-1was an upstream effector of ATF5 and partly activated UPR. In vitro, phenylephrine- (PE-) induced cardiomyocyte hypertrophy caused ATF5 upregulating rather than downregulating corresponding to the downregulation of PGC-1. The PGC-1/ATF5 axis mediated the UPRactivation 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 UPRthat mediates the cardioprotective role of THC in pathological cardiac hypertrophy.

Study Type : In Vitro Study

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