Cardiac-specific overexpression of HIF-1{alpha} prevents deterioration of glycolytic pathway and cardiac remodeling in streptozotocin-induced diabetic mice.
Cardiac-specific overexpression of HIF-1{alpha} prevents deterioration of glycolytic pathway and cardiac remodeling in streptozotocin-induced diabetic mice.
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DOI：
10.2353/ajpath.2010.091091
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发表时间：
2010-07
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影响因子：
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通讯作者：
Wanli Xue;Wanli Xue;Wanli Xue;Lu Cai;Lu Cai;Yi Tan;Yi Tan;P. Thistlethwaite;Y. J. Kang
中科院分区：
文献类型：
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作者：
Wanli Xue;Wanli Xue;Wanli Xue;Lu Cai;Lu Cai;Yi Tan;Yi Tan;P. Thistlethwaite;Y. J. Kang
在糖尿病患者心脏和实验糖尿病动物模型中有糖酵解和血管生成缺陷的报道。本研究的目的是确定过表达缺氧诱导因子(HIF)-1 α是否通过增加心肌糖酵解和血管生成来保护糖尿病小鼠的心肌损伤。用链脲佐菌素诱导心脏特异性过表达hif -1 α的转基因和年龄匹配的野生型对照小鼠诱导糖尿病。通过实时RT-PCR、Western blotting、酶分析和组织学分析检测心脏中葡萄糖转运蛋白、糖酵解酶、血管生成因子和心脏形态的变化。hif -1 α过表达可提高非糖尿病心脏中己糖激酶II （HK-II）蛋白水平和总HK活性，并阻止糖尿病心脏中HK-II mRNA、蛋白和总HK活性的下降。此外，在HIF转基因小鼠心脏中，葡萄糖转运蛋白I的减少，而葡萄糖转运蛋白4的减少，随着心肌ATP产生的恢复而恢复。hif -1 α的过度表达也使糖尿病的血管内皮生长因子浓度降低，同时维持心肌毛细血管密度，抑制心肌细胞肥大和心脏纤维化。因此，HIF-1 α的升高通过上调HIF-1靶基因，对糖尿病引起的糖代谢和血管生成损伤提供心脏保护。
Defective glycolysis and angiogenesis in the heart of diabetic patients and in experimental diabetic animal models have been reported. The aim of this study was to determine whether overexpression of hypoxia-inducible factor (HIF)-1alpha protects from myocardial injury in diabetic mice by increasing myocardial glycolysis and angiogenesis. Cardiac-specific HIF-1alpha-overexpressing transgenic and age-matched wild-type control mice were treated with streptozotocin to induce diabetes. Changes in glucose transporters, glycolytic enzymes, angiogenic factors and cardiac morphology were examined in the hearts by real-time RT-PCR, Western blotting, enzymatic assay, and histological assays. HIF-1alpha overexpression elevated hexokinase II (HK-II) protein level and total HK activity in nondiabetic heart and prevented the decreases in HK-II mRNA, protein, and total HK activity in diabetic heart. In addition, the reduction of glucose transporter I, but not glucose transporter 4, was restored in HIF transgenic mouse heart along with a recovery of myocardium ATP production. HIF-1alpha overexpression also normalized diabetes-reduced vascular endothelial growth factor concentration along with a sustained myocardial capillary density and an inhibition of cardiomyocyte hypertrophy and cardiac fibrosis. Therefore, elevation of HIF-1alpha provides a cardiac protection from diabetic-induced impairment in glucose metabolism and angiogenesis via up-regulation of HIF-1 target genes.