Therapeutic Angiogenesis Induced by Human Hepatocyte Growth Factor Gene in Rat Diabetic Hind Limb Ischemia Model: Molecular Mechanisms of Delayed Angiogenesis in Diabetes
Therapeutic Angiogenesis Induced by Human Hepatocyte Growth Factor Gene in Rat Diabetic Hind Limb Ischemia Model: Molecular Mechanisms of Delayed Angiogenesis in Diabetes
复制标题
人肝细胞生长因子基因在大鼠糖尿病后肢缺血模型中诱导治疗性血管生成：糖尿病延迟血管生成的分子机制
作者：
Y. Taniyama;R. Morishita;K. Hiraoka;M. Aoki;H. Nakagami;K. Yamasaki;Kunio Matsumoto;Toshikazu Nakamura;Y. Kaneda;T. Ogihara
背景--由于没有研究证明肝细胞生长因子（HGF）在糖尿病模型中的血管生成特性，我们研究了用HGF基因治疗糖尿病外周动脉疾病的可行性。方法和结果由于日本血凝病毒（HVJ）-脂质体法肌肉注射荧光素酶质粒比裸质粒注射效率高得多，我们采用HVJ-脂质体法将人HGF基因转染到糖尿病大鼠后肢模型中。如预期的，人HGF载体的转染导致血流量的显著增加，如通过激光多普勒成像和毛细血管密度评估的，甚至在糖尿病模型中，伴随着人HGF蛋白的检测。有趣的是，非糖尿病大鼠的血流量自然恢复程度明显高于糖尿病大鼠。因此，在体外培养系统中，我们进一步研究了糖尿病如何延迟血管生成的分子机制。重要的是，高糖处理内皮细胞导致基质金属蛋白酶（MMP）-1蛋白和ets-1在人主动脉内皮细胞的表达显着下降。同样，高糖显著降低内皮细胞HGF的mRNA和蛋白表达。高d-葡萄糖下调MMP-1和ets-1可能是由于HGF的显著减少，因为HGF刺激MMP-1的产生并激活ets-1。结论：总的来说，肌内注射人HGF质粒在大鼠糖尿病缺血后肢模型中诱导治疗性血管生成，作为外周动脉疾病的潜在治疗方法。糖尿病血管生成的延迟可能是由于高糖通过降低HGF而下调MMP-1和ets-1。
Background—Because no study has documented the angiogenic properties of hepatocyte growth factor (HGF) in a diabetes model, we examined the feasibility of gene therapy using HGF to treat peripheral arterial disease in diabetes. Methods and Results—Because intramuscular injection of luciferase plasmid by the hemagglutinating virus of Japan (HVJ)–liposome method had much higher efficiency than injection of naked plasmid, we used the HVJ-liposome method to transfect the human HGF gene into the rat diabetic hindlimb model. As expected, transfection of human HGF vector resulted in a significant increase in blood flow as assessed by laser Doppler imaging and capillary density, even in the diabetes model, accompanied by the detection of human HGF protein. Interestingly, the degree of natural recovery of blood flow was significantly greater in nondiabetic rats than in diabetic rats. Thus, in an in vitro culture system, we further studied the molecular mechanisms of how diabetes delayed angiogenesis. Importantly, high–d-glucose treatment of endothelial cells resulted in a significant decrease in matrix metalloproteinase (MMP)-1 protein and ets-1 expression in human aortic endothelial cells. Similarly, high d-glucose significantly decreased mRNA and protein of HGF in endothelial cells. Downregulation of MMP-1 and ets-1 by high d-glucose might be due to a significant decrease in HGF, because HGF stimulated MMP-1 production and activated ets-1. Conclusions—Overall, intramuscular injection of human HGF plasmid induced therapeutic angiogenesis in a rat diabetic ischemic hindlimb model as a potential therapy for peripheral arterial disease. The delay of angiogenesis in diabetes might be due to downregulation of MMP-1 and ets-1 through a decrease in HGF by high d-glucose.
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影响因子：
15.9
作者：
Murohara, T;Asahara, T;Isner, JM
通讯作者：
Isner, JM
影响因子：
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Y. Tsurumi;M. Kearney;Dongfen Chen;Marcy Silver;S. Takeshita;Jihong Yang;J. Symes;J. Isner
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影响因子：
37.8
作者：
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通讯作者：
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影响因子：
6
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通讯作者：
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37.8
作者：
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通讯作者：
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