Resveratrol improves left ventricular diastolic relaxation in type 2 diabetes by inhibiting oxidative/nitrative stress: in vivo demonstration with magnetic resonance imaging.
Resveratrol improves left ventricular diastolic relaxation in type 2 diabetes by inhibiting oxidative/nitrative stress: in vivo demonstration with magnetic resonance imaging.
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DOI：
10.1152/ajpheart.00489.2010
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发表时间：
2010-07
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通讯作者：
Hanrui Zhang;Brandon Morgan;B. Potter;Lixin Ma;K. Dellsperger;Z. Ungvari;Cuihua Zhang
中科院分区：
文献类型：
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作者：
Hanrui Zhang;Brandon Morgan;B. Potter;Lixin Ma;K. Dellsperger;Z. Ungvari;Cuihua Zhang
白藜芦醇是一种天然的植物酚，具有心脏保护作用。本研究旨在阐明白藜芦醇对糖尿病引起的心功能不全的保护机制。正常对照组（m-Lepr（db））和2型糖尿病（Lepr（db））小鼠口服白藜芦醇4 wk。在体MRI显示白藜芦醇通过增加Lepr（db）小鼠左心室舒张期峰值充盈率改善心功能。这种保护作用部分是由白藜芦醇在改善一氧化氮（NO）的产生和抑制心脏组织中的氧化/硝化应激的作用来解释的。白藜芦醇通过增强内皮型一氧化氮合酶（eNOS）表达增加NO生成，通过抑制NAD（P）H氧化酶活性和gp 91（phox）mRNA及蛋白表达减少O（2）（·-）生成。诱导型一氧化氮合酶（iNOS）抑制剂1400 W可抑制Lepr（db）小鼠硝基酪氨酸（N-Tyr）蛋白表达的增加。白藜芦醇降低Lepr（db）小鼠中N-Tyr和iNOS的表达。此外，在白藜芦醇处理的Lepr（db）小鼠中，TNF-α mRNA和蛋白表达以及NF-κB活化降低。TNF-α敲除的Lepr（db）小鼠（db（TNF-）/db（TNF-）小鼠）和NF-κB抑制剂MG-132处理的Lepr（db）小鼠均表现出NAD（P）H氧化酶活性和iNOS表达降低以及eNOS表达升高，而TNF-α处理的m-Lepr（db）小鼠表现出相反的作用。因此，白藜芦醇通过抑制氧化/硝化应激和改善NO可用性来防止心脏功能障碍。这种改善是由于白藜芦醇在抑制TNF-α诱导的NF-κB活化中的作用，因此随后抑制NAD（P）H氧化酶和iNOS的表达和活化以及增加2型糖尿病中eNOS的表达。
Resveratrol is a natural phytophenol that exhibits cardioprotective effects. This study was designed to elucidate the mechanisms by which resveratrol protects against diabetes-induced cardiac dysfunction. Normal control (m-Lepr(db)) mice and type 2 diabetic (Lepr(db)) mice were treated with resveratrol orally for 4 wk. In vivo MRI showed that resveratrol improved cardiac function by increasing the left ventricular diastolic peak filling rate in Lepr(db) mice. This protective role is partially explained by resveratrol's effects in improving nitric oxide (NO) production and inhibiting oxidative/nitrative stress in cardiac tissue. Resveratrol increased NO production by enhancing endothelial NO synthase (eNOS) expression and reduced O(2)(·-) production by inhibiting NAD(P)H oxidase activity and gp91(phox) mRNA and protein expression. The increased nitrotyrosine (N-Tyr) protein expression in Lepr(db) mice was prevented by the inducible NO synthase (iNOS) inhibitor 1400W. Resveratrol reduced both N-Tyr and iNOS expression in Lepr(db) mice. Furthermore, TNF-α mRNA and protein expression, as well as NF-κB activation, were reduced in resveratrol-treated Lepr(db) mice. Both Lepr(db) mice null for TNF-α (db(TNF-)/db(TNF-) mice) and Lepr(db) mice treated with the NF-κB inhibitor MG-132 showed decreased NAD(P)H oxidase activity and iNOS expression as well as elevated eNOS expression, whereas m-Lepr(db) mice treated with TNF-α showed the opposite effects. Thus, resveratrol protects against cardiac dysfunction by inhibiting oxidative/nitrative stress and improving NO availability. This improvement is due to the role of resveratrol in inhibiting TNF-α-induced NF-κB activation, therefore subsequently inhibiting the expression and activation of NAD(P)H oxidase and iNOS as well as increasing eNOS expression in type 2 diabetes.