SIRT2 counteracts primate cardiac aging via deacetylation of STAT3 that silences CDKN2B
SIRT2 counteracts primate cardiac aging via deacetylation of STAT3 that silences CDKN2B
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DOI：
10.1038/s43587-023-00486-y
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发表时间：
2023-10
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通讯作者：
Yanxia Ye;Kuan Yang;Haisong Liu;Yang Yu;Moshi Song;Daoyuan Huang;Jinghui Lei;Yiyuan Zhang;Zunpeng Liu;Qun Chu;Yanling Fan;Sheng Zhang;Yaobin Jing;C. R. Esteban;Si Wang;J. C. I. Belmonte;J. Qu;Weiqi Zhang;Guang-Hui Liu
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作者：
Yanxia Ye;Kuan Yang;Haisong Liu;Yang Yu;Moshi Song;Daoyuan Huang;Jinghui Lei;Yiyuan Zhang;Zunpeng Liu;Qun Chu;Yanling Fan;Sheng Zhang;Yaobin Jing;C. R. Esteban;Si Wang;J. C. I. Belmonte;J. Qu;Weiqi Zhang;Guang-Hui Liu
衰老是导致心脏病理生理变化的主要危险因素，但其内在机制在灵长类动物中尚未得到充分研究。在这项研究中，我们研究了老年食蟹猴心脏的肥厚和衰老表型，以及年轻和老年灵长类动物心脏的转录组学和蛋白质组学景观。SIRT2被认为是衰老猴子心脏中一个关键蛋白的减少，并且在人类多能干细胞衍生的心肌细胞中工程化的SIRT2缺失重现了灵长类动物心脏衰老的关键衰老特征。进一步的研究表明，人类心肌细胞中SIRT2的缺失导致STAT3的高乙酰化，从而转录激活cdkn2带，进而引发心肌细胞变性。心肌内注射表达SIRT2的慢病毒可改善小鼠年龄相关性心功能障碍。综上所述，我们的研究为解码灵长类动物心脏衰老提供了宝贵的资源，并确定了SIRT2-STAT3-CDKN2B调控轴作为人类心脏衰老和衰老相关心血管疾病的潜在治疗靶点。
Aging is a major risk factor contributing to pathophysiological changes in the heart, yet its intrinsic mechanisms have been largely unexplored in primates. In this study, we investigated the hypertrophic and senescence phenotypes in the hearts of aged cynomolgus monkeys as well as the transcriptomic and proteomic landscapes of young and aged primate hearts. SIRT2 was identified as a key protein decreased in aged monkey hearts, and engineered SIRT2 deficiency in human pluripotent stem cell-derived cardiomyocytes recapitulated key senescence features of primate heart aging. Further investigations revealed that loss of SIRT2 in human cardiomyocytes led to the hyperacetylation of STAT3, which transcriptionally activatedCDKN2Band, in turn, triggered cardiomyocyte degeneration. Intra-myocardial injection of lentiviruses expressing SIRT2 ameliorated age-related cardiac dysfunction in mice. Taken together, our study provides valuable resources for decoding primate cardiac aging and identifies the SIRT2–STAT3–CDKN2B regulatory axis as a potential therapeutic target against human cardiac aging and aging-related cardiovascular diseases.