科研成果:“SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy”

发布时间:2017-12-19

导读:本重点实验室主任刘德培院士课题组发现蛋白去乙酰化酶SIRT2可以通过调节代谢稳态抑制衰老相关心肌肥厚。题为 “SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy”的研究论文于2017年11月21日在线发表在《circulation》杂志上。 

文章链接:http://circ.ahajournals.org/content/136/21/2051.long。 

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    心血管疾病在全球范围内已经是威胁人类健康最主要的死亡因素。在65岁以上人群中,心血管疾病(如高血压和动脉粥样硬化及后续的心衰和中风)贡献了超过40%的死亡率。并且,超过80%的心血管疾病都发生在65岁以上人群中。因此,老龄本身就是心血管疾病最主要的危险因素。在老年心血管病人中,疾病预后随着年龄的增加也逐渐变差。但是,目前我们对衰老过程中心血管系统结构和功能变化的认识还不足。对衰老相关心脏疾病的深入认识有利于指导临床预防和治疗老年相关的心血管疾病,如心肌肥厚和心衰。 刘德培院士实验室长期致力于研究衰老相关重大疾病,尤其是心血管疾病。2016年,刘德培院士课题组揭示蛋白去酰化酶SIRT1可以抑制衰老相关的腹主动脉瘤(Circ Res. 2016 Oct 28;119(10):1076-1088.),参与能量限制对腹主动脉瘤的保护作用(J Exp Med. 2016 Oct 17;213(11):2473-2488.)。

    在本研究中,刘德培实验室发现参与衰老相关心肌肥厚的核心去乙酰化酶。作者以自然衰老和血管紧张素II诱导的衰老相关心肌肥厚为模型,发现衰老过程中增加的血管紧张素II可以激活c-Src激酶,而c-Src可以促进蛋白去乙酰化酶SIRT2的降解。蛋白去酰化酶SIRT2可以对组蛋白和非组蛋白进行去乙酰化从而参与到肿瘤、代谢、炎症等多个生理病理过程中。在本研究中发现SIRT2蛋白可以与激酶LKB1相互作用,在K48位点对LKB1去乙酰化,从而激活AMPK,从而调节代谢稳态来保护心功能,抑制衰老相关的心肌肥厚和心肌纤维化。同时,研究过程中还发现二甲双胍对AMPK的激活作用以及心肌肥厚的抑制作用都依赖于SIRT2蛋白。该研究进一步增加了我们对于衰老如何调节代谢相关的表观修饰酶从而促进衰老相关的心肌肥厚的认识。也提示SIRT2可能会成为治疗衰老相关心肌肥厚的潜在靶点,为进一步探索治疗衰老相关的心血管疾病提供了重要的理论基础。 

【摘要】: Background: Pathological cardiac hypertrophy induced by stresses such as aging and neurohumoral activation is an independent risk factor for heart failure and is considered a target for the treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the roles of SIRT2 in aging-related and angiotensin II (Ang II)–induced pathological cardiac hypertrophy. Methods: Male C57BL/6J wild-type and Sirt2 knockout mice were subjected to the investigation of aging-related cardiac hypertrophy. Cardiac hypertrophy was also induced by Ang II (1.3 mg/kg/d for 4 weeks) in male C57BL/6J Sirt2 knockout mice, cardiac-specificSIRT2 transgenic (SIRT2-Tg) mice, and their respective littermates (8 to ≈12 weeks old). Metformin (200 mg/kg/d) was used to treat wild-type and Sirt2 knockout mice infused with Ang II. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice. Results: SIRT2 protein expression levels were downregulated in hypertrophic hearts from mice. Sirt2 knockout markedly exaggerated cardiac hypertrophy and fibrosis and decreased cardiac ejection fraction and fractional shortening in aged (24-month-old) mice and Ang II–infused mice. Conversely, cardiac-specific SIRT2 overexpression protected the hearts against Ang II–induced cardiac hypertrophy and fibrosis and rescued cardiac function. Mechanistically, SIRT2 maintained the activity of AMP-activated protein kinase (AMPK) in aged and Ang II–induced hypertrophic hearts in vivo as well as in cardiomyocytes in vitro. We identified the liver kinase B1 (LKB1), the major upstream kinase of AMPK, as the direct target of SIRT2. SIRT2 bound to LKB1 and deacetylated it at lysine 48, which promoted the phosphorylation of LKB1 and the subsequent activation of LKB1-AMPK signaling. Remarkably, the loss of SIRT2 blunted the response of AMPK to metformin treatment in mice infused with Ang II and repressed the metformin-mediated reduction of cardiac hypertrophy and protection of cardiac function. Conclusions: SIRT2 promotes AMPK activation by deacetylating the kinase LKB1. Loss of SIRT2 reduces AMPK activation, promotes aging-related and Ang II–induced cardiac hypertrophy, and blunts metformin-mediated cardioprotective effects. These findings indicate that SIRT2 will be a potential target for therapeutic interventions in aging- and stress-induced cardiac hypertrophy. 

    刘德培院士和陈厚早副研究员为本研究共同通讯作者,刘德培课题组唐小强博士和2016级博士生陈小凤为本研究共同第一作者。本研究受到国家自然基金委重点项目、基金委优秀青年项目、教育部青年长江项目、中共组织部万人计划项目和中国医学科学院医学与健康科技创新工程等资助。 


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