CTRP3 alleviates mitochondrial dysfunction and oxidative stress injury in pathological cardiac hypertrophy by activating UPRmt via the SIRT1/ATF5 axis.
CTRP3 alleviates mitochondrial dysfunction and oxidative stress injury in pathological cardiac hypertrophy by activating UPRmt via the SIRT1/ATF5 axis.
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CTRP 3通过SIRT 1/ATF 5轴激活UPRmt来减轻病理性心肌肥大中的线粒体功能障碍和氧化应激损伤。
DOI：
10.1038/s41420-024-01813-x
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发表时间：
2024-01-26
影响因子：
7
通讯作者：
Yi, Wei
中科院分区：
文献类型：
--
作者：
Shi, Lei;Tan, Yanzhen;Zheng, Wenying;Cao, Guojie;Zhou, Haitao;Li, Panpan;Cui, Jun;Song, Yujie;Feng, Lele;Li, Hong;Shan, Wenju;Zhang, Bing;Yi, Wei
病理性心肌肥厚是心力衰竭的独立危险因素。线粒体蛋白质稳态的破坏在病理性心肌肥大中起着关键作用，然而，维持病理性心肌肥大中线粒体稳态的机制尚不清楚。在这项研究中，我们探讨了线粒体蛋白质稳态的调节机制，在病理性心肌肥厚。野生型（WT）小鼠，基因敲除小鼠，慢病毒转染过表达小鼠C1 q-肿瘤坏死因子相关蛋白-3（CTRP 3）的小鼠进行横向主动脉缩窄或假手术。4周后，检测心功能、线粒体功能和氧化应激损伤。对于机制研究，新生大鼠心肌细胞用小干扰RNA或相关基因的过表达质粒处理。与WT小鼠相比，CTRP 3过表达减弱了横主动脉缩窄（TAC）诱导的病理性心脏肥大、线粒体功能障碍和氧化应激损伤。TAC或Ang II导致UPRmt的代偿性激活，但这不足以抵消病理性心脏肥大。CTRP 3过表达在病理性心脏肥大期间进一步诱导UPRmt的激活，从而减轻病理性心脏肥大，而CTRP 3敲除或敲低抑制UPRmt。ATF 5是UPRmt的关键调节分子，因为ATF 5敲除阻止了TAC小鼠中CTRP 3的心脏保护作用。在体外，SIRT 1被鉴定为可能的下游CTRP 3效应分子，并且SIRT 1敲除阻断了CTRP 3的心脏保护作用。我们的研究结果还表明，ATF 5可能受到SIRT 1的调控。我们的研究表明，CTRP 3通过SIRT 1/ATF 5轴激活UPRmt病理性心肌肥大，从而减轻线粒体功能障碍和氧化应激损伤。
Pathological cardiac hypertrophy is an independent risk factor for heart failure. Disruption of mitochondrial protein homeostasis plays a key role in pathological cardiac hypertrophy; however, the mechanism of maintaining mitochondrial homeostasis in pathological cardiac hypertrophy remains unclear. In this study, we investigated the regulatory mechanisms of mitochondrial protein homeostasis in pathological cardiac hypertrophy. Wildtype (WT) mice, knockout mice, and mice transfected with lentivirus overexpressing mouse C1q-tumor necrosis factor-related protein-3 (CTRP3) underwent transverse aortic constriction or sham surgery. After 4 weeks, cardiac function, mitochondrial function, and oxidative stress injury were examined. For mechanistic studies, neonatal rat cardiomyocytes were treated with small interfering RNA or overexpression plasmids for the relevant genes. CTRP3 overexpression attenuated transverse aortic constriction (TAC) induced pathological cardiac hypertrophy, mitochondrial dysfunction, and oxidative stress injury compared to that in WT mice. TAC or Ang II resulted in compensatory activation of UPRmt, but this was not sufficient to counteract pathologic cardiac hypertrophy. CTRP3 overexpression further induced activation of UPRmt during pathologic cardiac hypertrophy and thereby alleviated pathologic cardiac hypertrophy, whereas CTRP3 knockout or knockdown inhibited UPRmt. ATF5 was a key regulatory molecule of UPRmt, as ATF5 knockout prevented the cardioprotective effect of CTRP3 in TAC mice. In vitro, SIRT1 was identified as a possible downstream CTRP3 effector molecule, and SIRT1 knockout blocked the cardioprotective effects of CTRP3. Our results also suggest that ATF5 may be regulated by SIRT1. Our study demonstrates that CTRP3 activates UPRmt via the SIRT1/ATF5 axis under pathological myocardial hypertrophy, thus attenuating mitochondrial dysfunction and oxidative stress injury.
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