Mouse Sirt3 promotes autophagy in AngII-induced myocardial hypertrophy through the deacetylation of FoxO1.
Mouse Sirt3 promotes autophagy in AngII-induced myocardial hypertrophy through the deacetylation of FoxO1.
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DOI：
10.18632/oncotarget.13429
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发表时间：
2016-12-27
期刊：
影响因子：
--
通讯作者：
Bu P
中科院分区：
文献类型：
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作者：
Li J;Chen T;Xiao M;Li N;Wang S;Su H;Guo X;Liu H;Yan F;Yang Y;Zhang Y;Bu P
Sirt3是一种依赖于NAD+的线粒体组蛋白去乙酰化酶，是哺乳动物Sirtuin家族中唯一被证实具有促进长寿作用的成员。已证明Sirt3的加工短形式靶向能量代谢和线粒体应激适应程序的许多介质。自噬作为一种动态循环机制，提供能量或代谢底物。在心脏应激引发的机制中，关于自噬是保护性反应还是有害反应，意见不一。在这里，通过用慢性血管紧张素II输注诱导Sirt3敲除小鼠心肌肥大四周，我们确定了Sirt3在心肌肥大和自噬中的作用。在这项研究中，与野生型小鼠相比，Sirt 3基因敲除小鼠的心脏功能恶化，自噬受损。更重要的是，通过慢病毒转染Sirt3的过表达通过促进自噬来减轻心肌细胞肥大。我们进一步证明了Sirt3可以与FoxO1结合并激活其脱乙酰化。随后，脱乙酰化FoxO1易位到细胞核，在那里它促进下游E3泛素连接酶，如肌肉环指1（MuRF 1）和肌肉萎缩F盒（MAFbx，Atrogin 1）。总之，这些结果表明，Sirt3激活是必不可少的，以改善自噬通量减少FoxO1的乙酰化修饰，这反过来又加剧心肌肥大。
Sirt3, a mitochondrial NAD+-dependent histone deacetylase, is the only member proven to promote longevity in mammalian Sirtuin family. The processed short form of Sirt3 has been demonstrated to target many mediators of energy metabolism and mitochondrial stress adaptive program. Autophagy serves as a dynamic recycling mechanism and provides energy or metabolic substrates. Among the mechanisms triggered by cardiac stress, opinions vary as to whether autophagy is a protective or detrimental response. Here, by inducing the Sirt3-knockout mice to myocardial hypertrophy with chronic angiotensin II infusion for four weeks, we determined the role of Sirt3 in myocardial hypertrophy and autophagy. In this study, the Sirt3-knockout mice developed deteriorated cardiac function and impaired autophagy compared to wild-type mice. What's more, the overexpression of Sirt3 by lentivirus transfection attenuated cardiomyocytes hypertrophy by promoting autophagy. We further demonstrated that Sirt3 could bind to FoxO1 and activate its deacetylation. Sequentially, deacetylated FoxO1 translocates to the nucleus where it facilitates downstream E3 ubiquitin ligases such as Muscle RING Finger 1 (MuRF1) and muscle atrophy F-box (MAFbx, Atrogin1). Altogether, these results revealed that Sirt3 activation is essential to improve autophagy flux by reducing the acetylation modification on FoxO1, which in turn alleviates myocardial hypertrophy.