Asymmetric Dimethylarginine (ADMA), Genetic Variation, and Cardiovascular Disease

越来越多的证据表明，除了炎症和血脂异常的途径有助于动脉粥样硬化，内皮功能障碍和早发冠心病（CHD）的基础过程。然而，很少有研究探讨氧化应激，内皮功能障碍和冠心病之间的相互关系。不对称二甲基精氨酸（ADMA）是一种内源性一氧化氮合酶（NOS）抑制剂，最近已成为心血管疾病的潜在新的风险标志物。 大部分ADMA由酶二甲基精氨酸二甲氨基水解酶（DDAH）代谢，细胞氧化应激增加抑制组织中的DDAH活性，导致ADMA水平持续升高。 ADMA的积累和NO合成的减少导致内皮功能障碍，并且还启动和促进与动脉粥样硬化形成有关的过程。 血浆ADMA水平与CHD的几个危险因素有关;然而，关于ADMA的预测价值、DDAH基因的遗传变异以及男性和女性CHD的预期风险的数据迄今为止仍然有限。 本提案的目的是在两项大型前瞻性队列研究（护士健康研究（NHS）和卫生专业人员随访研究（HPFS））中研究血浆ADMA水平作为CHD的新生化预测因子。 这两项研究都有超过22年的重复饮食和生活方式问卷调查数据，从NHS的32，826名女性和HPFS的18，225名男性中收集的血液样本，以及巢式病例对照研究，其中生物样本先前在非致命性心肌梗死或致命性CHD的事件病例中存档，年龄和吸烟匹配对照。 该提案的具体目的是：1）在男性和女性的巢式病例对照设置中检查血浆ADMA与CHD事件风险之间的前瞻性关系; 2）利用现有的前瞻性数据来检查生活方式、饮食和其他健康因素与血浆ADMA之间的相互关系，以阐明潜在的机制;以及3.）研究DDAH基因的遗传变异与男性和女性血浆ADMA水平和冠心病风险的关系。 这些发现可能导致新的治疗干预，抑制ADMA的作用，防止动脉粥样硬化和心血管疾病的进展。

Growing evidence suggests that pathways in addition to inflammation and dyslipidemia contribute to the Underlying processes of atherosclerosis, endothelial dysfunction, and premature coronary heart disease (CHD). However, few studies have examined the interrelations between oxidative stress, endothelial dysfunction, and CHD. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), and has recently emerged as a potential novel risk marker for cardiovascular disease. The majority of ADMA is metabolized by the enzyme, dimethylarginine dimethylaminohydrolase (DDAH), and increased cellular oxidative stress inhibits DDAH activity in the tissues, which leads to sustained levels of ADMA. Accumulation of ADMA and reduced NO systhesis leads to endothelial dysfunction and also initiates and promotes processes involved with atherogenesis. Plasma ADMA levels have been associated with several risk factors of CHD; however, data on the predictive value of ADMA, genetic variation in the DDAH gene, and the prospective risk of CHD in men and women have thus far been limited. The goal of this proposal is to investigate plasma ADMA levels as a novel biochemical predictor of CHD among two large prospective cohort studies: the Nurses Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Both studies have over 22 years of repeated dietary and lifestyle questionnaire data, blood samples collected from 32, 826 women in NHS and 18,225 men in HPFS, and nested case-control studies with biological specimens previously archived among incident cases of nonfatal myocardial infarction or fatal CHD, and age and smoking matched controls. The specific aims of this proposal are to: 1) examine the prospective relationship between plasma ADMA and risk of incident CHD in nested case-control settings among men and women; 2.) utilize the existing prospective data to examine interrelations between lifestyle, dietary, and other health factors, and plasma ADMA to elucidate potential mechanisms; and 3.) examine the genetic variation on the DDAH gene with plasma ADMA levels and risk of CHD in both men and women. These findings may lead to new therapeutic interventions which inhibit the effects of ADMA and prevent the progression of atherosclerosis and cardiovascular disease.