Ex vivo gene transferring of human dimethylarginine dimethylaminohydrolase-2 improved endothelial dysfunction in diabetic rat aortas and high glucose-treated endothelial cells
Ex vivo gene transferring of human dimethylarginine dimethylaminohydrolase-2 improved endothelial dysfunction in diabetic rat aortas and high glucose-treated endothelial cells
复制标题
人二甲基精氨酸二甲氨基水解酶-2 的离体基因转移改善了糖尿病大鼠主动脉和高葡萄糖处理的内皮细胞的内皮功能障碍。
DOI：
10.1016/j.atherosclerosis.2009.08.035
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发表时间：
2010-03-01
期刊：
影响因子：
5.3
通讯作者：
Xiong, Yan
中科院分区：
文献类型：
--
作者：
Lu, Chang-Wu;Guo, Zheng;Xiong, Yan
目的：不对称二甲基精氨酸（ADMA）水平升高是内皮功能障碍的独立危险因素。二甲基精氨酸二甲氨基水解酶（DDAH）是降解内源性ADMA的关键酶。本研究的目的是确定是否抑制DDAH 2的表达将牵连与糖尿病相关的内皮功能障碍，并进一步探讨是否腺病毒介导的DDAH 2基因过表达可以改善高血糖诱导的内皮dysfunction.Methods：糖尿病模型由腹腔注射链脲佐菌素雄性SD大鼠。构建了由巨细胞病毒启动子驱动的人DDAH 2基因重组腺病毒载体，并在大鼠血管内皮细胞中过表达。结果：与对照组相比，糖尿病大鼠血管DDAH 2表达明显降低，DDAH活性降低，血管内皮依赖性舒张功能受损，血清ADMA浓度升高。高糖可抑制DDAH 2表达和DDAH活性，增加ADMA含量，抑制NO合成。DDAH 2过表达不仅能改善糖尿病大鼠血管内皮功能障碍，而且能减轻高血糖引起的血管内皮细胞DDAH/ADMA//NO通路的改变。结论：DDAH 2过表达可改善高血糖引起的血管内皮功能障碍。提示靶向调控血管内皮DDAH 2基因可能成为治疗糖尿病内皮功能障碍的新途径。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。
Objectives: Elevated level of asymmetric dimethylarginine (ADMA) is an independent risk factor for endothelial dysfunction. Dimethylarginine dimethylaminohydrolase (DDAH) is the key enzyme responsible for the degradation of endogenous ADMA. The purposes of this study were to determine whether suppressed DDAH2 expression would implicate in endothelial dysfunction associated with diabetes mellitus and further to investigate whether adenovirus-mediated DDAH2 gene overexpression could improve the hyperglycemia-induced endothelial dysfunction.Methods: Diabetic model was induced by intraperitoneal injection of streptozotocin to male Sprague-Dawley rats. Recombinant adenoviral vector encoding human DDAH2 gene driven by a cytomegalovirus promoter was constructed to overexpress hDDAH2 gene in isolated rat aortas and endothelial cells. Changes in DDHA/ADMA/nitric oxide (NO) pathway in diabetic rats and high glucose-treated endothelial cells were examined.Results: DDAH2 expression was distinctly suppressed, which was accompanied by inhibited DDAH activity and impaired endothelium-dependent relaxation in aortas, and elevated ADMA concentrations in serum of diabetic rats compared to control rats. Suppressions of DDAH2 expression and DDAH activity, accumulation of ADMA, and inhibition of NO synthesis were observed in high glucose-treated endothelial cells. DDAH2 overexpression not only improved endothelial dysfunction in diabetic aortas but also attenuated hyperglycemia-induced changes in DDAH/ADMA//NO pathway in endothelial cells.Conclusion: These results indicate that suppression of DDAH2 expression contributes to hyperglycemia-induced endothelial dysfunction, which can be improved by DDAH2 overexpression. This study suggests that targeted modulation of DDAH2 gene in vascular endothelium may be a novel approach for the treatment of endothelial dysfunction in diabetes mellitus. (C) 2009 Elsevier Ireland Ltd. All rights reserved.