Novel PGC-1α/ATF5 Axis Partly Activates UPR(mt) and Mediates Cardioprotective Role of Tetrahydrocurcumin in Pathological Cardiac Hypertrophy.
Novel PGC-1α/ATF5 Axis Partly Activates UPR(mt) and Mediates Cardioprotective Role of Tetrahydrocurcumin in Pathological Cardiac Hypertrophy.
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新型 PGC-1α/ATF5 轴部分激活 UPRmt 并介导四氢姜黄素在病理性心脏肥大中的心脏保护作用
DOI：
10.1155/2020/9187065
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发表时间：
2020
影响因子：
--
通讯作者：
Yi W
中科院分区：
文献类型：
--
作者：
Zhang B;Tan Y;Zhang Z;Feng P;Ding W;Wang Q;Liang H;Duan W;Wang X;Yu S;Liu J;Yi D;Sun Y;Yi W
线粒体解折叠蛋白反应（UPRmt）能有效地对抗病理性心肌肥厚，改善线粒体功能。然而，具体的激活机制和药物，可以有效地激活心肌中的UPRmt尚未阐明。本研究旨在探讨UPRmt对四氢姜黄素（tetrahydrocurcumin，THC）预防病理性心肌肥厚的调节作用及其分子机制。将雄性C57 BL/6 J野生型（WT）小鼠分为对照组和试验组，对照组进行4周的假治疗，试验组进行横向主动脉缩窄（TAC）手术。对照组和试验组动物在TAC手术后口服THC（50 mg/kg）4周;对照假治疗组和TAC组口服等量的生理盐水。随后，在这些小鼠中评估氧化应激和UPRmt标志物，并测试心脏肥大、纤维化和心脏功能。采用靶向增殖物激活受体-γ共激活因子（PGC）-1α和转录激活因子5（ATF 5）的小干扰RNA（siRNA）研究UPRmt的激活机制。与TAC操作的WT小鼠相比，THC补充剂部分上调UPRmt效应子并抑制TAC诱导的氧化应激，从而显著减轻收缩功能障碍、心脏肥大和纤维化。此外，PGC-1α敲低减弱了UPRmt的激活和THC的心脏保护作用。在正常条件下，在新生大鼠心肌细胞中检测PGC-1α和ATF 5之间的相互作用。结果表明，PGC-1α是ATF 5的上游效应子，部分激活UPRmt。在体外实验中，苯肾上腺素（PE）诱导的心肌细胞肥大导致ATF 5上调而不是下调，对应于PGC-1α的下调。PGC-1α/ATF 5轴介导了THC的UPRmt激活和抗逆作用。总的来说，本研究提供了第一个证据，即PGC-1和ATF 5可以形成一个信号传导轴，部分激活UPRmt，介导THC在病理性心脏肥大中的心脏保护作用。
Mitochondrial unfolding protein response (UPRmt) effectively resists the pathological cardiac hypertrophy and improves the mitochondrial function. However, the specific activation mechanism and drugs that can effectively activate UPRmt in the cardiac muscle are yet to be elucidated. The aim of this study was to determine the regulation role of UPRmt 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 UPRmt 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 UPRmt activation mechanism. THC supplement partly upregulated UPRmt 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 UPRmt 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 UPRmt. 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 UPRmt 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 UPRmt that mediates the cardioprotective role of THC in pathological cardiac hypertrophy.
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影响因子：
37.8
作者：
Schiattarella GG;Hill JA
通讯作者：
Hill JA
四氢瓜蛋白可预防小鼠镉诱导的高血压，升高动脉刚度和血管重塑。
影响因子：
3.7
作者：
Sangartit W;Kukongviriyapan U;Donpunha W;Pakdeechote P;Kukongviriyapan V;Surawattanawan P;Greenwald SE
通讯作者：
Greenwald SE
影响因子：
37.8
作者：
Diguet N;Trammell SAJ;Tannous C;Deloux R;Piquereau J;Mougenot N;Gouge A;Gressette M;Manoury B;Blanc J;Breton M;Decaux JF;Lavery GG;Baczkó I;Zoll J;Garnier A;Li Z;Brenner C;Mericskay M
通讯作者：
Mericskay M
DOI：
10.3390/molecules20010185
发表时间：
2014-12-24
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Aggarwal BB;Deb L;Prasad S
通讯作者：
Prasad S
影响因子：
37.8
作者：
Moens, An L.;Takimoto, Eiki;Kass, David A.
通讯作者：
Kass, David A.