Cardiomyocyte GTP Cyclohydrolase 1 Protects the Heart Against Diabetic Cardiomyopathy.
Cardiomyocyte GTP Cyclohydrolase 1 Protects the Heart Against Diabetic Cardiomyopathy.
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DOI：
10.1038/srep27925
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发表时间：
2016-06-13
影响因子：
4.6
通讯作者：
Ge ZD
中科院分区：
文献类型：
--
作者：
Wu HE;Baumgardt SL;Fang J;Paterson M;Liu Y;Du J;Shi Y;Qiao S;Bosnjak ZJ;Warltier DC;Kersten JR;Ge ZD
糖尿病心肌病会增加心力衰竭和死亡的风险。目前，临床上尚无有效的方法来预防其发展。在这里，我们报告通过遗传和药理学方法减少心脏 GTP 环化水解酶 1 (GCH1) 的降解，可以保护心脏免受糖尿病性心肌病的影响。使用链脲佐菌素在 C57BL/6 野生型小鼠和心肌细胞特异性过度表达 GCH1 的转基因小鼠中诱导糖尿病心肌病，并给予对照动物柠檬酸盐缓冲液。我们发现，糖尿病诱导的心脏 GCH1 蛋白降解导致 C57BL/6 小鼠心脏不良重塑和功能障碍，同时四氢生物蝶呤、二聚体和磷酸化神经元一氧化氮合酶、肌浆网 Ca2+ 处理蛋白、细胞内 [Ca2+]i 和肌浆网 Ca2+ 含量减少，磷酸化 p-38 丝裂原激活蛋白激酶增加和超氧化物的产生。有趣的是，GCH-1 过度表达消除了糖尿病的这些有害影响。此外，我们发现 MG 132（一种 26S 蛋白酶体抑制剂）可以保留心脏 GCH1 蛋白，并改善糖尿病期间的心脏重塑和功能障碍。这项研究加深了我们对糖尿病心脏功能受损的认识，确定了 GCH1 作为心脏重塑和功能的调节剂，并揭示了糖尿病心肌病的新治疗靶点。
Diabetic cardiomyopathy increases the risk of heart failure and death. At present, there are no effective approaches to preventing its development in the clinic. Here we report that reduction of cardiac GTP cyclohydrolase 1 (GCH1) degradation by genetic and pharmacological approaches protects the heart against diabetic cardiomyopathy. Diabetic cardiomyopathy was induced in C57BL/6 wild-type mice and transgenic mice with cardiomyocyte-specific overexpression of GCH1 with streptozotocin, and control animals were given citrate buffer. We found that diabetes-induced degradation of cardiac GCH1 proteins contributed to adverse cardiac remodeling and dysfunction in C57BL/6 mice, concomitant with decreases in tetrahydrobiopterin, dimeric and phosphorylated neuronal nitric oxide synthase, sarcoplasmic reticulum Ca2+ handling proteins, intracellular [Ca2+]i, and sarcoplasmic reticulum Ca2+ content and increases in phosphorylated p-38 mitogen-activated protein kinase and superoxide production. Interestingly, GCH-1 overexpression abrogated these detrimental effects of diabetes. Furthermore, we found that MG 132, an inhibitor for 26S proteasome, preserved cardiac GCH1 proteins and ameliorated cardiac remodeling and dysfunction during diabetes. This study deepens our understanding of impaired cardiac function in diabetes, identifies GCH1 as a modulator of cardiac remodeling and function, and reveals a new therapeutic target for diabetic cardiomyopathy.