ADMA对人冠脉内皮细胞的损伤及作为冠心病风险标志物的研究

The environmental and genetic factors contribute to the risk of coronary heart disease (CAD). With the social economic development, the incidence and mortality of CAD around the developing countries continue to rise. Therefore, screening clinical laboratory biomarkers which were used to forecast the expected risk of CAD is important for improve the life quality of the citizens. Endothelial dysfunction is an important risk factor for CAD. The features of endothelial dysfunction are the decreased expression of the endothelial nitric oxide synthase (eNOS), and the reduced bioavailability of the nitric oxide (NO). ADMA which lead to the endothelial dysfunction is a residue of proteolysis of L-arginine-methylated proteins. Many studies have demonstrated that the ditrimental effect of ADMA on human umbilical vein endothelial cells, and on animal coronary artery endothelial cells, but lack of studies on coronary artery endothelial cells. In addition, the relationship between plasma ADMA level and the risk of CAD still needs supports from experimental evidences. In this study, we firstly investigate the ditrimental effect of ADMA on the human coronary endothelium. The relationship between the plasma ADMA level, the mutations of coding-exon of DDAH gene and expected risk of CAD were studied by using the study of large-scale randomized controlled trials. The results of our study will provide the clinical laboratory biomarkers which were used to forecast the expected risk of CAD.

冠心病的发生与环境和遗传因素有密切关系。随着社会经济的发展，特别是在发展中国家冠心病的发病率和死亡率均不断升高。因此筛选预测冠心病发病风险的生物标志物对提高人民生活质量非常重要。 内皮细胞功能损伤是冠心病发生的重要危险因素。内皮功能损伤主要表现为内皮型一氧化氮合酶表达的下降，一氧化氮释放或生物利用度降低。ADMA是人体内蛋白质甲基化过程的产物，具有导致内皮细胞损伤的作用。ADMA对人脐动脉内皮细胞和动物冠状动脉内皮细胞的损伤作用研究较多，但缺乏对人冠状动脉内皮细胞作用的研究。此外，血浆ADMA浓度与冠心病的发病风险的关联性还缺乏充分的证据。 本课题首先研究ADMA对人冠状动脉内皮细胞损伤的相关机制。并通过大样本随机对照实验进一步明确血浆ADMA浓度，代谢基因DDAH编码外显子变异与冠心病发生风险的关系。研究结果可为预测冠心病的发生风险提供临床检验生物标志物。

ADMA是人体中L-精氨酸甲基化过程的衍生物。ADMA通过与L-精氨酸竞争，抑制eNOS的活性，导致NO的表达降低，使内皮细胞损伤。.在这项研究中我们关注以下问题：1）L-瓜氨酸可以改善由ADMA导致的猪冠状动脉功能损伤和相应的机制。2) ADMA对人冠状动脉内皮细胞的损伤机制及AVE3085的保护作用。3) 血清ADMA浓度与冠心病风险的关系。4）DDAH 2基因−449C/G 多态性与冠心病风险的关系和与血浆ADMA水平的关系。5) 血清ADMA水平与早发性冠心病的关系。6) MTHFR 基因与先天性心脏病的关系。.总之，ADMA诱导的内皮损伤是通过减少NO的生物利用度，增加ROS的产生，下调eNOS 和 p-eNOS1177的表达并导致细胞凋亡实现的。L-瓜氨酸和AVE3085可以改善ADMA损伤的内皮功能。ADMA是重要的心血管疾病生物标志物。