Yu Huijing, Zhang Fang, Yan Pengyi, Zhang Shasha, Lou Yingmei, Geng Zilong, Li Zixuan, Zhang Yan, Xu Yuejuan, Lu Yanan, Chen Chen, Wang Daowen, Zhu Wei, Hu Xinyang, Wang Jian'an, Zhuang Tao, Zhang Yuzhen, Wu Gengze, Liu Junling, Zeng Chunyu, Pu William T, Sun Kun, Zhang Bing
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.).
Circulation. 2021 May 18;143(20):2007-2022. doi: 10.1161/CIRCULATIONAHA.120.050812. Epub 2021 Mar 5.
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.
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 knockout mice. We acutely abolished LARP7 in mature cardiomyocytes by Cas9-mediated 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.
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 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.
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.
心力衰竭（HF）是发病和死亡的主要原因之一，其患病率持续上升。LARP7（La核糖核蛋白结构域家族成员7）是一种主要调节因子，控制DNA损伤反应和RNA聚合酶II（RNAPII）暂停途径，但其在HF发病机制中的作用尚未完全明确。
我们评估了LARP7在人类HF以及非人类灵长类和小鼠HF模型中的表达。为了研究LARP7在心脏中的功能，我们构建了全身和心脏特异性敲除小鼠。我们通过Cas9介导的体细胞敲除在成熟心肌细胞中急性消除LARP7。我们使用腺相关病毒9型和共济失调毛细血管扩张突变蛋白（ATM）抑制剂在心肌细胞中过表达LARP7。在小鼠心肌梗死模型中测试了LARP7调节途径在HF中的治疗潜力。
在衰竭的人类心脏以及非人类灵长类和小鼠心肌梗死后的心脏中，LARP7显著下调。衰竭心脏中LARP7水平较低与活性氧升高有关，活性氧激活了ATM介导的DNA损伤反应途径，并促进了LARP7的泛素化和降解。小鼠中的组成性敲除导致线粒体生物发生受损、心肌发育不全和妊娠中期致死。心脏特异性失活导致线粒体生物发生缺陷、氧化磷酸化受损、氧化应激升高，并在4个月大时出现HF。这些异常伴随着沉默信息调节因子2同源物1（SIRT1）稳定性和脱乙酰酶活性降低，这损害了SIRT1介导的氧化磷酸化和能量代谢基因的转录，并削弱了心脏功能。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，可显著改善受损心脏的功能。
LARP7通过调节SIRT1稳态和活性，对线粒体生物发生、能量产生和心脏功能至关重要。由于ATM途径的激活，患病心脏中LARP7的减少导致HF发病机制，而在受损心脏中恢复LARP7可提供心肌保护。这些结果确定了ATM-LARP7-SIRT1途径是HF治疗干预的靶点。
