Resveratrol Improves Cardiac Contractility following Trauma-Hemorrhage by Modulating Sirt1
Resveratrol Improves Cardiac Contractility following Trauma-Hemorrhage by Modulating Sirt1
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DOI：
10.2119/molmed.2011.00365
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发表时间：
2012-02-01
影响因子：
5.7
通讯作者：
Raju, Raghavan
中科院分区：
文献类型：
--
作者：
Jian, Bixi;Yang, Shaolong;Raju, Raghavan
线粒体在细胞代谢动态平衡中起着至关重要的作用。我们最近的研究基于c-Myc和Sirt1(酵母沉默信息调节因子2的哺乳动物同源基因)表达的相互关系及其在线粒体生物发生和功能中的作用，发现创伤-出血(T-H)后Sirt1蛋白的表达显著下调，c-Myc的表达上调。已知Sirt1的激活剂可以改善线粒体的功能，而自然产生的Sirt1白藜芦醇(RSV)通过增加其与NAD+和乙酰化底物的亲和力而显著提高Sirt1的活性。在这项研究中，我们测试了T-H后RSV的有益作用及其对Sirt1表达的影响。大鼠接受T-H或假手术。复苏10min后静脉注射RSV(8 mg/kg体重)或赋形剂，复苏后2 h处死大鼠。Sirt1抑制剂Sirtinol在RSV给药前5分钟给药。测定心肌收缩功能(+/-dp/dt)，检测心肌组织Sirt1、PGC-1α、c-Myc、胞浆细胞色素C表达和ATP水平。RSV治疗后左心功能明显改善(P<；0.05)，Sirt1(P<；0.05)和PGC-1α(P<；0.05)表达显著增加，c-Myc降低(P<；0.05)。我们还观察到T-H-RSV组心脏ATP含量显著升高，胞浆细胞色素C降低，血浆肿瘤坏死因子-α降低。RSV的有益作用可被sirtinol消除，表明Sirt1介导的作用。我们的结论是，RSV可能是T-H术后复苏液的有用补充。在线地址：http://www.molmed.org doi：10.2119/molmed.2011.00365
Mitochondria play a critical role in metabolic homeostasis of a cell. Our recent studies, based on the reported interrelationship between c-Myc and Sirt1 (mammalian orthologue of yeast sir2 (silent information regulator 2)) expression and their role in mitochondrial biogenesis and function, demonstrated a significant downregulation of Sirt1 protein expression and an upregulation of c-Myc following trauma-hemorrhage (T-H). Activators of Sirt1 are known to improve mitochondrial function and the naturally occurring Sirt1 resveratrol (RSV) has been shown to significantly increase Sirt1 activity by increasing its affinity to both NAD+ and the acetylated substrate. In this study we tested the salutary effect of RSV following T-H and its influence on Sirt1 expression. Rats were subjected to T-H or sham operation. RSV (8 mg/kg body weight, intravenously) or vehicle was administered 10 min after the onset of resuscitation, and the rats were killed 2 h following resuscitation. Sirtinol, a Sirt1 inhibitor, was administered 5 min prior to RSV administration. Cardiac contractility (+/- dP/dt) was measured and heart tissue was tested for Sirt1, Pgc-1 alpha, c-Myc, cytosolic cytochrome C expression and ATP level. Leff ventricular function, after T-H, was improved (P < 0.05) following RSV treatment, with significantly elevated expression of Sirt1 (P < 0.05) and Pgc-1 alpha (P < 0.05), and decreased c-Myc (P < 0.05). We also observed significantly higher cardiac ATP content, declined cytosolic cytochrome C and decreased plasma tumor necrosis factor-alpha in the T-H-RSV group. The salutary effect due to RSV was abolished by sirtinol, indicating a Sirt1-mediated effect. We conclude that RSV may be a useful adjunct to resuscitation fluid following T-H. Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00365