LARP7 通过增强线粒体生物发生来预防心力衰竭,Circulation

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LARP7 通过增强线粒体生物发生来预防心力衰竭
Circulation ( IF 35.5 ) Pub Date : 2021-03-05 , DOI: 10.1161/circulationaha.120.050812
Huijing Yu ₁ , Fang Zhang ₁ , Pengyi Yan ₁ , Shasha Zhang ₁ , Yingmei Lou ₁ , Zilong Geng ₁ , Zixuan Li ₁ , Yan Zhang , Yuejuan Xu ₁ , Yanan Lu ₁ , Chen Chen ₂ , Daowen Wang ₂ , Wei Zhu ₃ , Xinyang Hu , Jian'an Wang ₃ , Tao Zhuang ₄ , Yuzhen Zhang _{4,

5} , Gengze Wu ₆ , Junling Liu , Chunyu Zeng ₆ , William T Pu _{7,

8} , Kun Sun ₁ , Bing Zhang ₁

Affiliation

Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Xin Hua Hospital, Shanghai Jiao Tong University, China (H.J.Y., F.Z., P.Y.Y., S.S.Z., Y.M.L., Z.L.G., Z.X.L., Y.J.X., Y.N.L., K.S., B.Z.).
Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (C.C., D.W.W.).
Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, China (W.Z., X.Y.H., J.A.W.).
Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, China (T.Z., Y.Z.Z.).
Renji-Med Clinical Stem Cell Research Center, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, China (Y.Z.).
Department of Cardiology, Chongqing Institute of Cardiology, Chongqing Cardiovascular Clinical Research Center, Daping Hospital, The Third Military Medical University, China (G.Z.W., C.Y.Z.).
Department of Cardiology, Boston Children's Hospital, MA (W.T.P).
Harvard Stem Cell Institute, Cambridge, MA (W.T.P).

背景：心力衰竭 (HF) 是发病率和死亡率的主要原因之一，并且其患病率持续上升。LARP7（La 核糖核蛋白域家族成员 7）是控制 DNA 损伤反应和 RNAPII（RNA 聚合酶 II）暂停途径的主要调节因子，但其在 HF 发病机制中的作用尚不完全清楚。方法：我们评估了 LARP7 在人类 HF 和非人灵长类动物和小鼠 HF 模型。为了研究 LARP7 在心脏中的功能，我们生成了全局和心脏特异性LARP7敲除小鼠。我们通过 Cas9 介导的LARP7急剧消除了成熟心肌细胞中的LARP7体细胞敲除。我们使用腺相关病毒血清型 9 和 ATM（共济失调毛细血管扩张突变蛋白）抑制剂在心肌细胞中过表达 LARP7。在小鼠心肌梗塞模型中测试了 LARP7 调节通路在 HF 中的治疗潜力。结果：LARP7 在心肌梗塞后衰竭的人类心脏和非人类灵长类动物和鼠类心脏中显着下调。衰竭心脏中低 LARP7 水平与升高的活性氧物质有关，后者激活了 ATM 介导的 DNA 损伤反应途径并促进了 LARP7 泛素化和降解。本构 LARP7小鼠中的敲除导致线粒体生物合成受损、心肌发育不全和妊娠中期致死率。心脏特异性失活导致线粒体生物合成缺陷、氧化磷酸化受损、氧化应激升高和 4 个月大时出现 HF。这些异常伴随着 SIRT1（沉默交配型信息调节 2 同源物 1）稳定性和脱乙酰酶活性降低，这会损害 SIRT1 介导的氧化磷酸化和能量代谢基因转录，并削弱心脏功能。通过腺相关病毒介导的 LARP7 表达或小分子 ATM 抑制剂在心肌梗死后恢复 LARP7 表达可显着改善受损心脏的功能。结论：LARP7 对线粒体生物合成、能量产生、通过调节 SIRT1 稳态和活性来改善心脏功能。由于 ATM 通路的激活，患病心脏中 LARP7 的减少有助于 HF 发病机制，而在受损心脏中恢复 LARP7 可赋予心肌保护。这些结果将 ATM-LARP7-SIRT1 通路确定为 HF 治疗干预的目标。

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LARP7 Protects Against Heart Failure by Enhancing Mitochondrial Biogenesis

Background:Heart failure (HF) is among the leading causes of morbidity and mortality, and its prevalence continues to rise. LARP7 (La ribonucleoprotein domain family member 7) is a master regulator that governs the DNA damage response and RNAPII (RNA polymerase II) pausing pathway, but its role in HF pathogenesis is incompletely understood.Methods:We assessed LARP7 expression in human HF and in nonhuman primate and mouse HF models. To study the function of LARP7 in heart, we generated global and cardiac-specific LARP7 knockout mice. We acutely abolished LARP7 in mature cardiomyocytes by Cas9-mediated LARP7 somatic knockout. We overexpressed LARP7 in cardiomyocytes using adeno-associated virus serotype 9 and ATM (ataxia telangiectasia mutated protein) inhibitor. The therapeutic potential of LARP7-regulated pathways in HF was tested in a mouse myocardial infarction model.Results:LARP7 was profoundly downregulated in failing human hearts and in nonhuman primate and murine hearts after myocardial infarction. Low LARP7 levels in failing hearts were linked to elevated reactive oxygen species, which activated the ATM-mediated DNA damage response pathway and promoted LARP7 ubiquitination and degradation. Constitutive LARP7 knockout in mouse resulted in impaired mitochondrial biogenesis, myocardial hypoplasia, and midgestational lethality. Cardiac-specific inactivation resulted in defective mitochondrial biogenesis, impaired oxidative phosphorylation, elevated oxidative stress, and HF by 4 months of age. These abnormalities were accompanied by reduced SIRT1 (silent mating type information regulation 2 homolog 1) stability and deacetylase activity that impaired SIRT1-mediated transcription of genes for oxidative phosphorylation and energy metabolism and dampened cardiac function. Restoring LARP7 expression after myocardial infarction by either adeno-associated virus–mediated LARP7 expression or small molecule ATM inhibitor substantially improved the function of injured heart.Conclusions:LARP7 is essential for mitochondrial biogenesis, energy production, and cardiac function by modulating SIRT1 homeostasis and activity. Reduction of LARP7 in diseased hearts owing to activation of the ATM pathway contributes to HF pathogenesis and restoring LARP7 in the injured heart confers myocardial protection. These results identify the ATM-LARP7-SIRT1 pathway as a target for therapeutic intervention in HF.

更新日期：2021-03-05

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