Resveratrol, an activator of SIRT1, upregulates sarcoplasmic calcium ATPase and improves cardiac function in diabetic cardiomyopathy
Resveratrol, an activator of SIRT1, upregulates sarcoplasmic calcium ATPase and improves cardiac function in diabetic cardiomyopathy
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DOI：
10.1152/ajpheart.00418.2009
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发表时间：
2010-03-01
影响因子：
4.8
通讯作者：
Gupta, M.
中科院分区：
文献类型：
--
作者：
Sulaiman, M.;Matta, M. J.;Gupta, M.
Sulaiman M，Matta MJ，Sunderesan NR，Gupta MP，Periasamy M，Gupta M.白藜芦醇是SIRT 1的激活剂，上调肌浆钙ATP酶并改善糖尿病心肌病的心功能。Am J Physiol Heart Circ Physiol 298：H833-H843，2010.首次发表于2009年12月11日; doi：10.1152/ajpheart.00418.2009。肌浆钙ATP酶（SERCA 2a）表达减少已被证明在糖尿病心肌病的心功能障碍中起重要作用。然而，SERCA 2a抑制的机制尚不清楚。本研究旨在研究白藜芦醇（RSV），一种SIRT 1的有效激活剂，对慢性1型糖尿病患者心功能和SERCA 2a表达的影响。成年雄性小鼠注射链脲佐菌素（STZ），并喂食常规饮食或富含RSV的饮食。STZ给药导致心脏功能进行性下降，与SERCA 2a和SIRT 1蛋白水平显著降低和胶原沉积增加相关; RSV治疗这些小鼠在改善SERCA 2a表达和心脏功能方面具有巨大的有益作用。在培养的心肌细胞中，RSV恢复SERCA 2启动子活性，否则在高葡萄糖培养基中被高度抑制。RSV的保护作用取决于其激活沉默信息调节因子（SIRT）1的能力。在心肌细胞中，发现SIRT 1的过表达足以以剂量依赖性方式激活SERCA 2启动子。相反，用SIRT 1拮抗剂splitomycin预处理心肌细胞，阻断了RSV的这些有益作用。此外，还发现SIRT 1敲除（+/-）小鼠对STZ诱导的SERCA 2a mRNA下降更敏感。数据表明，在慢性糖尿病中，1）心脏SIRT 1的酶活性降低，这有助于SERCA 2a的表达降低，和2）通过SIRT 1的活化，RSV增强SERCA 2a的表达并改善心脏功能。
Sulaiman M, Matta MJ, Sunderesan NR, Gupta MP, Periasamy M, Gupta M. Resveratrol, an activator of SIRT1, upregulates sarcoplasmic calcium ATPase and improves cardiac function in diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 298: H833-H843, 2010. First published December 11, 2009; doi:10.1152/ajpheart.00418.2009.-Reduced sarcoplasmic calcium ATPase (SERCA2a) expression has been shown to play a significant role in the cardiac dysfunction in diabetic cardiomyopathy. The mechanism of SERCA2a repression is, however, not known. This study was designed to examine the effect of resveratrol (RSV), a potent activator of SIRT1, on cardiac function and SERCA2a expression in chronic type 1 diabetes. Adult male mice were injected with streptozotocin (STZ) and fed with either a regular diet or a diet enriched with RSV. STZ administration produced progressive decline in cardiac function, associated with markedly reduced SERCA2a and SIRT1 protein levels and increased collagen deposition; RSV treatment to these mice had a tremendous beneficial effect both in terms of improving SERCA2a expression and on cardiac function. In cultured cardiomyocytes, RSV restored SERCA2 promoter activity, which was otherwise highly repressed in high-glucose media. Protective effects of RSV were found to be dependent on its ability to activate Silent information regulator (SIRT) 1. In cardiomyocytes, overexpression of SIRT1 was found sufficient to activate SERCA2 promoter in a dose-dependent manner. In contrast, pretreatment of cardiomyocytes with SIRT1 antagonist, splitomycin, blocked these beneficial effects of RSV. In addition, SIRT1 knockout (+/-) mice were also found to be more sensitive to STZ-induced decline in SERCA2a mRNA. The data demonstrate that, in chronic diabetes, 1) the enzymatic activity of cardiac SIRT1 is reduced, which contributes to reduced expression of SERCA2a and 2) through activation of SIRT1, RSV enhances expression of SERCA2a and improves cardiac function.