Inhibition of superoxide generation and associated nitrosative damage is involved in metallothionein prevention of diabetic cardiomyopathy
Inhibition of superoxide generation and associated nitrosative damage is involved in metallothionein prevention of diabetic cardiomyopathy
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DOI：
10.2337/diabetes.54.6.1829
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发表时间：
2005-06-01
期刊：
影响因子：
7.7
通讯作者：
Kang, YJ
中科院分区：
文献类型：
--
作者：
Cai, L;Wang, JX;Kang, YJ
金属硫蛋白预防糖尿病心肌病的机制尚不清楚。本研究旨在测试亚硝化损伤的抑制是否与金属硫蛋白预防糖尿病心肌病有关。通过单次腹膜内注射链脲佐菌素 (STZ) 治疗心脏特异性金属硫蛋白过表达转基因 (MT-TG) 小鼠和野生型同窝对照小鼠，均患上糖尿病。然而，通过组织病理学和超微结构检查、血清肌酸磷酸激酶和心脏血流动力学分析揭示的糖尿病心肌病的发展仅在野生型小鼠中显着观察到，而在 MT-TG、STZ 治疗后 2 周和 6 个月的糖尿病小鼠中未观察到。仅在野生型糖尿病小鼠的心脏中检测到超氧化物和 3-硝基酪氨酸 (3-NT) 的形成，3-NT 是过亚硝酸盐诱导的蛋白质损伤的标志物。此外，将来自野生型和MT-TG小鼠的心肌细胞的原代培养物暴露于脂多糖/肿瘤坏死因子-a以产生细胞内过氧亚硝酸盐。在野生型心肌细胞中观察到 3-NT 形成和细胞毒性增加，但在 MT-TG 心肌细胞中未观察到。尿酸盐（一种过氧亚硝酸盐特异性清除剂）或 Mn(111) 四聚体 1-甲基 4-吡啶基五氯化卟啉 (MnTMPyP)（一种超氧化物歧化酶模拟物）可显着抑制 3-NT 的形成，并显着防止细胞毒性。因此，这些结果表明，金属硫蛋白对糖尿病心肌病的预防至少部分是通过抑制超氧化物生成和相关亚硝化损伤介导的。
The mechanisms of metallothionein prevention of diabetic cardiomyopathy are largely unknown. The present study was performed to test whether inhibition of nitrosative damage is involved in metallothionein prevention of diabetic cardiomyopathy. Cardiac-specific metallothionein-overexpressing transgenic (MT-TG) mice and wildtype littermate controls were treated with streptozotocin (STZ) by a single intraperitoneal injection, and both developed diabetes. However, the development of diabetic cardiomyopathy, revealed by histopathological and ultrastructural examination, serum creatine phosphokinase, and cardiac hemodynamic analysis, was significantly observed only in the wild-type, but not in MT-TG, diabetic mice 2 weeks and 6 months after STZ treatment. Formations of superoxide and 3-nitrotyrosine (3-NT), a marker for peroxynitrite-induced protein damage, were detected only in the heart of wild-type diabetic mice. Furthermore, primary cultures of cardiomyocytes from wild-type and MT-TG mice were exposed to lipopolysaccharide/tumor necrosis factor-a for generating intracellular peroxynitrite. Increases in 3-NT formation and cytotoxicity were observed in wild-type, but not in MT-TG, cardiomyocytes. Either urate, a peroxynitrite-specific scavenger, or Mn(111) tetralds 1-methyl 4-pyridyl porphyrin pentachloride (MnTMPyP), a superoxide dismutase mimic, significantly inhibited the formation of 3-NT along with a significant prevention of cytotoxicity. These results thus suggest that metallothionein prevention of diabetic cardiomyopathy is mediated, at least in part, by suppression of superoxide generation and associated nitrosative damage.