刘德培院士课题组在《European Heart Journal》 杂志发表研究论文“Sirt4 accelerates Ang II-induced pathological cardiac hypertrophy by inhibiting manganese superoxide dismutase activity （2016）”。

心血管疾病已经成为全球范围了威胁人类健康的主要因素之一。据《2015年中国心血管病报告》，我们国家心血管疾病死亡率占比已经超过40%。随着人口老年化不断加剧，预计这一比例在今后一段时间将持续增加。心衰是一种范围广，影响因素多，病因复杂，治疗策略有限的心血管疾病。心肌肥厚是心衰的一个重要病理基础。高血压、心肌梗死、冠心病等可诱发病理性心肌肥厚。随着心肌肥厚的发展，最终导致心力衰竭和猝死。心肌肥厚和心衰的发生机制和治疗策略研究一直是心血管领域的重要研究课题。刘德培院士课题组4月20日，刘德培院士课题组在著名心脏杂志《European Heart Journal》上发表重要研究成果，揭示抗衰老蛋白家族Sirtuin成员Sirt3和Sirt4协调调控线粒体氧化应激来控制病理性心肌肥厚的发展。

在这篇题为《Sirt4 accelerates Ang II-induced pathological cardiac hypertrophy by inhibiting manganese superoxide dismutase activity》的文章中，研究人员发现线粒体蛋白Sirt4可以和另外一个线粒体成员Sirt3相互作用，抑制Sirt3与其底物MnSOD相互结合，从而抑制Sirt3对MnSOD进行去乙酰化，降低MnSOD抗氧化活性，在病理情况下增加线粒体氧化应激水平。并且在Sirt4敲除小鼠和Sirt4心脏特异性转基因小鼠证明Sirt4是促进心肌肥厚的重要因子，颠覆以往认为Sirtuin都是抑制心血管疾病的观点。氧化应激是心肌肥厚和心衰重要的发生机制，但最近十年来临床研究发现广谱的抗氧化剂并不能改善心血管疾病的预后。近年来有科学家和临床医生提出，针对线粒体氧化应激进行干预可能成为心血管疾病治疗的新的突破口。尽管在动物水平已经有一些证据证明针对线粒体氧化应激可以改善心血管疾病，但是目前的机制尚不明确。

刘德培院士这项工作证明Sirt3-Sirt4协调线粒体氧化应激，可能为将来设计针对线粒体抗氧化应激类药物提供新思路。该研究发表后被心血管顶级杂志Circulation主编Joseph A. Hill作为亮点就行了点评（Eur Heart J. 2016 May 30.doi.org/10.1093/eurheartj/ehw199）。刘德培院士课题组一直以心血管疾病发生机制和治疗策略研究作为重点内容之一，前期在动脉粥样性血管疾病，心肌肥厚/心力衰竭发生机制和治疗策略研究方面的系列研究已分别发表在Circulation, Nature Communications, Journal of Clinical Investigation, Circulation Research, Hypertension等杂志。这篇工作发表在European Heart Journal （影响因子15.2）上，是刘德培院士在该领域取得的又一进展。

【摘要】：Abstract

AIMS:

Oxidative stress contributes to the development of cardiac hypertrophy and heart failure. One of the mitochondrial sirtuins, Sirt4, is highly expressed in the heart, but its function remains unknown. The aim of the present study was to investigate the role of Sirt4 in the pathogenesis of pathological cardiac hypertrophy and the molecular mechanism by which Sirt4 regulates mitochondrial oxidative stress.

METHODS AND RESULTS:

Male C57BL/6 Sirt4 knockout mice, transgenic (Tg) mice exhibiting cardiac-specific overexpression of Sirt4 (Sirt4-Tg) and their respective controls were treated with angiotensin II (Ang II, 1.1 mg/kg/day). At 4 weeks, hypertrophic growth of cardiomyocytes, fibrosis and cardiac function were analysed. Sirt4 deficiency conferred resistance to Ang II infusion by significantly suppressing hypertrophic growth, and the deposition of fibrosis. In Sirt4-Tg mice, aggravated hypertrophy and reduced cardiac function were observed compared with non-Tg mice following Ang II treatment. Mechanistically, Sirt4 inhibited the binding of manganese superoxide dismutase (MnSOD) to Sirt3, another member of the mitochondrial sirtuins, and increased MnSOD acetylation levels to reduce its activity, resulting in elevated reactive oxygen species (ROS) accumulation upon Ang II stimulation. Furthermore, inhibition of ROS with manganese 5, 10, 15, 20-tetrakis-(4-benzoic acid) porphyrin, a mimetic of SOD, blocked the Sirt4-mediated aggravation of the hypertrophic response in Ang II-treated Sirt4-Tg mice.

CONCLUSIONS:

Sirt4 promotes hypertrophic growth, the generation of fibrosis and cardiac dysfunction by increasing ROS levels upon pathological stimulation. These findings reveal a role of Sirt4 in pathological cardiac hypertrophy, providing a new potential therapeutic strategy for this disease.

相关结果已发表于《European Heart Journal（Eur Heart J）》 杂志（2016，doi.org/10.1093/eurheartj/ehw138），其作者为刘德培院士课题组博士研究生罗玉璇、唐小强，重点室陈厚早副教授、刘德培院士是本文的通讯作者。该研究工作得到了以下基金的支持：国家自然科学基金(81422002, 91339201, 31271227, and 31571193)，国家科技支撑计划 (2013YQ0309230502 and 2014BAI02B01)。

Figure：Manganese 5, 10, 15, 20-tetrakis-(4-benzoic acid) porphyrin abolishes the Sirt4-mediated pro-hypertrophic effect. (A) heart weight to body weight and heart weight/tibia length ratios in non-transgenic and Sirt4-transgenic mice following MnTBAP or/and Ang II infusion for 4 weeks. n = 12. (B) Ejection fraction and fractional shortening of non-transgenic and Sirt4-transgenic mice following MnTBAP or/and Ang II infusion. n = 10–23. (C) Histological analysis of heart sections from non-transgenic and Sirt4-transgenic mice following MnTBAP or/and Ang II infusion. Heart cross-sections were stained with haematoxylin-eosin (top row; scale bars, 1 mm), wheat germ agglutinin (second row; scale bars, 40 μm), and picrosirius red (third and fourth row; scale bars, 50 μm). (D and E) Quantification of the cardiomyocyte cross-sectional area (D) and fibrotic area (E) in non-transgenic and Sirt4-transgenic mice following MnTBAP or/and Ang II infusion. n = 10–15. MnT, MnTBAP.

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