Metallothionein prevents diabetes-induced deficits in cardiomyocytes by inhibiting reactive oxygen species production.
Metallothionein prevents diabetes-induced deficits in cardiomyocytes by inhibiting reactive oxygen species production.
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DOI：
10.2337/diabetes.52.3.777
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发表时间：
2003-03
期刊：
影响因子：
7.7
通讯作者：
Gang Ye;Naira S. Metreveli;Jun Ren;P. Epstein
中科院分区：
文献类型：
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作者：
Gang Ye;Naira S. Metreveli;Jun Ren;P. Epstein
许多糖尿病患者的心肌收缩力受损，不能用高血压和动脉粥样硬化来解释。这种心肌病可能是由于器官损伤，如纤维化，或直接损害心肌细胞。已经提出活性氧物质（ROS）有助于这种损伤。为了解决这些假设，我们检测了从对照心脏、糖尿病OVE 26心脏和过表达抗氧化蛋白金属硫蛋白（MT）的糖尿病心脏中分离的单个心肌细胞的收缩性、Ca（2+）处理和ROS水平。我们的数据显示，与对照组相比，糖尿病心肌细胞表现出显著降低的峰值缩短，延长的缩短/再延长的持续时间，降低的最大缩短/再延长的速度，以及减缓细胞内Ca（2+）衰减。过度表达MT可以防止糖尿病引起的这些缺陷。此外，高糖和血管紧张素II促进糖尿病心肌细胞中ROS的产生显著增加。MT的慢性过度表达或急性在体外治疗与黄素蛋白抑制剂diphenyleneiodonium或血管紧张素II I型受体拮抗剂氯沙坦消除了过量的ROS生产糖尿病心肌细胞。这些数据表明，糖尿病在个体肌细胞水平上诱导损伤。损伤可归因于ROS的产生，糖尿病通过血管紧张素II和黄素蛋白酶依赖性途径增加ROS的产生。
Many individuals with diabetes experience impaired cardiac contractility that cannot be explained by hypertension and atherosclerosis. This cardiomyopathy may be due to either organ-based damage, such as fibrosis, or to direct damage to cardiomyocytes. Reactive oxygen species (ROS) have been proposed to contribute to such damage. To address these hypotheses, we examined contractility, Ca(2+) handling, and ROS levels in individual cardiomyocytes isolated from control hearts, diabetic OVE26 hearts, and diabetic hearts overexpressing antioxidant protein metallothionein (MT). Our data showed that diabetic myocytes exhibited significantly reduced peak shortening, prolonged duration of shortening/relengthening, and decreased maximal velocities of shortening/relengthening as well as slowed intracellular Ca(2+) decay compared with control myocytes. Overexpressing MT prevented these defects induced by diabetes. In addition, high glucose and angiotensin II promoted significantly increased generation of ROS in diabetic cardiomyocytes. Chronic overexpression of MT or acute in vitro treatment with the flavoprotein inhibitor diphenyleneiodonium or the angiotensin II type I receptor antagonist losartan eliminated excess ROS production in diabetic cardiomyocytes. These data show that diabetes induces damage at the level of individual myocyte. Damage can be attributed to ROS production, and diabetes increases ROS production via angiotensin II and flavoprotein enzyme-dependent pathways.