LARP7 Protects Against Heart Failure by Enhancing Mitochondrial Biogenesis
LARP7 Protects Against Heart Failure by Enhancing Mitochondrial Biogenesis
复制标题
LARP7 通过增强线粒体生物发生来预防心力衰竭
DOI：
10.1161/circulationaha.120.050812
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发表时间：
2021-05-18
期刊：
影响因子：
37.8
通讯作者：
Zhang, Bing
中科院分区：
文献类型：
--
作者：
Yu, Huijing;Zhang, Fang;Zhang, Bing
背景：心力衰竭（HF）是发病率和死亡率的主要原因之一，其患病率持续上升。LARP 7（La ribonucleoprotein domain family member 7）是一个主调节器，支配DNA损伤反应和RNAPII（RNA polymerase II）暂停通路，但其在HF发病机制中的作用是不完全understood.Methods：我们评估LARP 7在人类HF和非人灵长类动物和小鼠HF模型中的表达。为了研究LARP 7在心脏中的功能，我们产生了全局和心脏特异性LARP 7敲除小鼠。我们通过Cas9介导的LARP 7体细胞敲除在成熟心肌细胞中急性消除LARP 7。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LARP 7。LARP 7调节途径在HF的治疗潜力进行了测试，在小鼠心肌梗死model.Results：LARP 7是深刻下调失败的人的心脏和非人灵长类动物和小鼠心肌梗死后的心脏。衰竭心脏中的低LARP 7水平与升高的活性氧有关，活性氧激活ATM介导的DNA损伤反应途径并促进LARP 7泛素化和降解。组成型LARP 7敲除小鼠导致线粒体生物合成受损、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合成缺陷、氧化磷酸化受损、氧化应激升高和4月龄时的HF。这些异常伴随着SIRT 1（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，从而损害SIRT 1介导的氧化磷酸化和能量代谢基因转录，并抑制心脏功能。无论是腺相关病毒介导的LARP 7表达或小分子ATM抑制剂恢复LARP 7表达心肌梗死后大大提高了受损heart.Conclusions的功能：LARP 7是必不可少的线粒体生物合成，能源生产，并通过调节SIRT 1的稳态和活动的心脏功能。由于ATM途径的激活，患病心脏中LARP 7的减少有助于HF发病机制，并且在受损心脏中恢复LARP 7赋予心肌保护。这些结果鉴定了ATM-LARP 7-SIRT 1通路作为HF中治疗干预的靶标。
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.