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

不对称二甲基精氨酸 (ADMA)、遗传变异和心血管疾病

• 批准号: 8018104
• 负责人: Jennifer K Pai
• 金额: $ 25.22万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018104
• 关键词: Age; Alcohol consumption; Archives; Arginine; Atherosclerosis; Biochemical; Biological; Blood specimen; Body mass index; C-reactive protein; Cardiovascular Diseases; Cardiovascular system; Cohort Studies; Congestive Heart Failure; Coronary heart disease; Data; Diabetes Mellitus; Dietary Factors; Disease Progression; Dyslipidemias; Enzymes; Erectile dysfunction; Event; Functional disorder; Future; Genes; Genetic Polymorphism; Genetic Variation; Goals; Haplotypes; Health; Health Professional; Hypertension; Inflammation; Inflammatory; Insulin Resistance; Intake; Interleukin-6; International; Lead; Life Style; Link; Lipids; Maps; Measures; Mediator of activation protein; Metabolism; Myocardial Infarction; N,N-dimethylarginine; Nested Case-Control Study; Nitric Oxide Synthase; Nurses' Health Study; Oxidative Stress; Pathway interactions; Peripheral arterial disease; Plasma; Predictive Value; Prevention; Process; Public Health; Questionnaires; Recording of previous events; Risk; Risk Factors; Risk Marker; Smoking; Specimen; Stroke; Tissues; Tumor Necrosis Factor Receptor; Variant; Waist-Hip Ratio; Woman; atherogenesis; cardiovascular disorder risk; cardiovascular risk factor; case control; dimethylargininase; follow-up; heart disease risk; hypercholesterolemia; improved; inflammatory marker; inhibitor/antagonist; innovation; insulin sensitivity; lifestyle factors; men; novel; novel therapeutic intervention; premature; premature atherosclerosis; prevent; prospective

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.

越来越多的证据表明，除了炎症和血脂异常外，其他途径也参与了动脉粥样硬化、内皮功能障碍和早发冠心病(CHD)的潜在过程。然而，很少有研究考察氧化应激、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)是一氧化氮合酶(NOS)的内源性抑制物，近年来已成为心血管疾病潜在的新危险标记物。大多数ADMA是由二甲基精氨酸二甲氨基水解酶(DDAH)代谢的，细胞内氧化应激的增加抑制了组织中DDAH的活性，从而导致ADMA的持续水平。ADMA的积聚和NO合成的减少导致内皮功能障碍，也启动和促进了与动脉粥样硬化相关的过程。血浆ADMA水平与冠心病的几个危险因素相关；然而，到目前为止，关于ADMA的预测价值、DDAH基因的遗传变异以及男性和女性患CHD的预期风险的数据有限。这项建议的目的是在两项大型前瞻性队列研究中，研究血浆ADMA水平作为冠心病的新的生化预测指标：护士健康研究(NHS)和卫生专业人员随访研究(HPFS)。这两项研究都有超过22年的重复饮食和生活方式问卷数据，从NHS的32,826名女性和HPFS的18,225名男性采集的血液样本，以及嵌套的病例对照研究，其中包括先前在非致命性心肌梗死或致命性CHD事件中存档的生物样本，以及年龄和吸烟匹配的对照组。这项建议的具体目的是：1)在嵌套病例对照环境中，研究男性和女性血浆ADMA与冠心病发病风险之间的预期关系；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；检测男性和女性DDAH基因的遗传变异与血浆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措施，抑制ADMA的效果，防止动脉粥样硬化和心血管疾病的进展。