Activation of SIRT1, a class III histone deacetylase, contributes to fructose feeding-mediated induction of the alpha-myosin heavy chain expression.
Activation of SIRT1, a class III histone deacetylase, contributes to fructose feeding-mediated induction of the alpha-myosin heavy chain expression.
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DOI：
10.1152/ajpheart.01339.2007
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发表时间：
2008-03
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影响因子：
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通讯作者：
Jyothish B. Pillai;Martin Chen;Senthilkumar B. Rajamohan;S. Samant;V. Pillai;Madhu Gupta;Mahesh P. Gupta-Mahesh
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文献类型：
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作者：
Jyothish B. Pillai;Martin Chen;Senthilkumar B. Rajamohan;S. Samant;V. Pillai;Madhu Gupta;Mahesh P. Gupta-Mahesh
果糖喂养已被证明可诱导心脏α-肌球蛋白重链（MHC）的表达，并保护心脏免受缺血和再灌注介导的细胞损伤。本研究旨在探讨这种糖对MHC基因表达和心脏保护作用的机制。用6-丙基-2-硫氧嘧啶（PTU）饮食或PTU与富含果糖的饮食组合喂养成年小鼠。PTU处理使动物甲状腺功能减退，导致心脏α-MHC完全被β-MHC同种型取代。在PTU饮食中添加果糖导致α-MHC同种型的再表达达到显著水平。当PTU饮食与白藜芦醇（sirtuin（SIRT）1脱乙酰酶的激动剂）组合时，也观察到类似的α-MHC表达诱导。对这些动物心脏裂解物的分析表明，果糖喂养增加了NAD与NADH的比率和心脏SIRT 1水平，从而表明SIRT 1在果糖介导的α-MHC亚型活化中的作用。为了分析SIRT 1对MHC亚型表达的直接影响，我们产生了在心脏中表达SIRT 1的转基因小鼠。用PTU饮食治疗这些转基因小鼠并没有像在非转基因动物中那样导致α-MHC的消失。SIRT 1过表达还在瞬时转染试验中激活了α-MHC基因启动子，从而证实了SIRT 1在诱导α-MHC表达中的作用。果糖喂养也减弱了MHC亚型的转变，并阻断了与压力超负荷相关的心脏肥大反应，这再次与心脏SIRT 1水平的诱导相关。这些结果表明，果糖喂养通过诱导SIRT 1脱乙酰酶来保护心脏，并突出了其在诱导α-MHC基因表达中的作用。
Fructose feeding has been shown to induce the cardiac alpha-myosin heavy chain (MHC) expression and protect the heart from ischemia- and reperfusion-mediated cell injury. This study was designed to investigate the mechanism involved in the effect of this sugar on MHC gene expression and cardiac protection. Adult mice were fed with a 6-propyl-2-thiouracil (PTU) diet or PTU combined with a fructose-rich diet. PTU treatment made animals hypothyroid and that resulted in total replacement of cardiac alpha-MHC with the beta-MHC isoform. Addition of fructose in the PTU diet led to reexpression of the alpha-MHC isoform to a significant level. Similar induction of alpha-MHC expression was also seen when PTU diet was combined with resveratrol, an agonist of sirtuin (SIRT) 1 deacetylase. Analysis of heart lysate of these animals indicated that fructose feeding augmented the NAD-to-NADH ratio and the cardiac SIRT1 levels, thus suggesting a role of SIRT1 in fructose-mediated activation of alpha-MHC isoform. To analyze a direct effect of SIRT1 on MHC isoform expression, we generated transgenic mice expressing SIRT1 in the heart. Treatment of these transgenic mice with PTU diet did not lead to disappearance of alpha-MHC, as it did in the nontransgenic animals. SIRT1 overexpression also activated the alpha-MHC gene promoter in transient transfection assays, thus confirming a role of SIRT1 in the induction of alpha-MHC expression. Fructose feeding also attenuated the MHC isoform shift and blocked the cardiac hypertrophy response associated with pressure overload, which was again associated with the induction of cardiac SIRT1 levels. These results demonstrate that fructose feeding protects the heart by induction of the SIRT1 deacetylase and highlight its role in the induction of alpha-MHC gene expression.