Resveratrol inhibition of inducible nitric oxide synthase in skeletal muscle involves AMPK but not SIRT1
Resveratrol inhibition of inducible nitric oxide synthase in skeletal muscle involves AMPK but not SIRT1
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DOI：
10.1152/ajpendo.00530.2010
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发表时间：
2011-11-01
影响因子：
5.1
通讯作者：
Marette, Andre
中科院分区：
文献类型：
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作者：
Centeno-Baez, Carolina;Dallaire, Patrice;Marette, Andre
Centeno-Baez C、Dallaire P、Marette A。白藜芦醇对骨骼肌中诱导型一氧化氮合酶的抑制作用涉及 AMPK，但不涉及 SIRT1。 Am J Physiol Endocrinol Metab 301：E922-E930，2011。首次发表于 2011 年 8 月 2 日； doi: 10.1152/ajpendo.00530.2010。植物源性多酚白藜芦醇 (RSV) 调节寿命和新陈代谢，人们认为这些作用很大程度上是通过激活脱乙酰酶 SIRT1 介导的。然而，RSV 也会激活细胞能量传感器 AMP 激活蛋白激酶 (AMPK)。我们之前曾报道过 AMPK 激活剂抑制诱导型一氧化氮合酶 (iNOS)，这是内毒素血症和肥胖症中胰岛素抵抗的关键促炎介质。本研究的目的是评估 RSV 是否抑制胰岛素靶组织中 iNOS 的诱导，并确定 SIRT1 和 AMPK 激活在此效应中的作用。我们发现，RSV（40 mg/kg ip）治疗可降低内毒素（LPS）攻击小鼠骨骼肌和白色脂肪组织中 iNOS 的诱导和 NO 的产生，但不会降低肝脏中的 iNOS 诱导和 NO 产生。多酚的这种作用在体外得到重现，其中 RSV (10-80 μM) 强烈抑制细胞因子/LPS 处理的 L6 肌细胞和 3T3-L1 脂肪细胞中 iNOS 蛋白的诱导和 NO 的产生。然而，没有观察到RSV 对FAO 肝细胞中iNOS 诱导的影响。使用 SIRT1 抑制剂的进一步研究表明，脱乙酰酶不参与 RSV 对 iNOS 的作用。与此形成鲜明对比的是，RSV 激活 L6 肌细胞中的 AMPK，使用化合物 C 或 RNA 干扰减弱其激活部分阻断了 RSV 对 NO 产生的抑制作用。这些结果表明，RSV 通过涉及 AMPK 但不涉及 SIRT1 激活的机制特异性抑制肌肉中 iNOS 的诱导。 RSV 的这种抗炎作用可能有助于这种植物多酚的治疗效果。
Centeno-Baez C, Dallaire P, Marette A. Resveratrol inhibition of inducible nitric oxide synthase in skeletal muscle involves AMPK but not SIRT1. Am J Physiol Endocrinol Metab 301: E922-E930, 2011. First published August 2, 2011; doi: 10.1152/ajpendo.00530.2010.The plant-derived polyphenol resveratrol (RSV) modulates life span and metabolism, and it is thought that these effects are largely mediated by activating the deacetylase enzyme SIRT1. However, RSV also activates the cell energy sensor AMP-activated protein kinase (AMPK). We have previously reported that AMPK activators inhibit inducible nitric oxide synthase (iNOS), a key proinflammatory mediator of insulin resistance in endotoxemia and obesity. The aim of this study was to evaluate whether RSV inhibits iNOS induction in insulin target tissues and to determine the role of SIRT1 and AMPK activation in this effect. We found that RSV (40 mg/kg ip) treatment decreased iNOS induction and NO production in skeletal muscle and white adipose tissue, but not in liver, of endotoxin (LPS)-challenged mice. This effect of the polyphenol was recapitulated in vitro, where RSV (10-80 mu M) robustly inhibited iNOS protein induction and NO production in cytokine/LPS-treated L6 myocytes and 3T3-L1 adipocytes. However, no effect of RSV was observed on iNOS induction in FAO hepatocytes. Further studies using inhibitors of SIRT1 revealed that the deacetylase enzyme is not involved in RSV action on iNOS. In marked contrast, RSV activates AMPK in L6 myocytes, and blunting its activation using Compound C or RNA interference partly blocked the inhibitory effect of RSV on NO production. These results show that RSV specifically inhibits iNOS induction in muscle through a mechanism involving AMPK but not SIRT1 activation. This anti-inflammatory action of RSV likely contributes to the therapeutic effect of this plant polyphenol.