Oxidative stress and aortic valve disease

氧化应激与主动脉瓣疾病

• 批准号: 8116548
• 负责人: Jordan D Miller
• 金额: $ 24.9万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2013-06-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8116548
• 关键词: Animals; Aortic Valve Stenosis; Apolipoprotein E; Apoptotic; Arterial Fatty Streak; Atherosclerosis; Award; Biological Availability; Calcified; Calcium; Cells; Cholesterol; Clinical Trials; Collagen; Conflict (Psychology); Confocal Microscopy; Data; Development; Effectiveness; Enzyme Uncoupling; Enzymes; Exhibits; Functional disorder; Genetic; Goals; Histologic; Human; Hypertension; Inflammation; Laboratories; Lead; Lesion; Link; Lipids; Magnetic Resonance Imaging; Manganese Superoxide Dismutase; Mentors; Mitochondria; Molecular; Mus; N,N-dimethylarginine; Nitric Oxide; Nitric Oxide Synthase; Nodule; Operative Surgical Procedures; Osteoblasts; Osteoclasts; Oxidases; Oxidative Stress; Pathogenesis; Patients; Phase; Plasma; Play; Population; Process; Production; Reactive Oxygen Species; Risk Factors; Role; Smoking; Superoxide Dismutase; Superoxides; Time; United States; Ursidae Family; aortic valve; aortic valve disorder; aortic valve replacement; base; blood lipid; cofactor; dimethylargininase; enzyme activity; human NOS3 protein; hypercholesterolemia; imaging modality; inhibitor/antagonist; insight; laser capture microdissection; male; novel; novel strategies; overexpression; prevent; sex; tetrahydrobiopterin; treatment effect

Replacement of the aortic valve is the primary treatment for patients with symptomatic, calcific aortic valve stenosis (AVS), and is the most common valvular surgical procedure performed worldwide. Stenotic valves are histologically similar to atherosclerotic lesions, and the applicant's laboratory has shown significant ncreases in superoxide in atherosclerotic lesions and stenotic valves in hypercholesterolemic mice {Idlr-/-/ApoBIOO/100). However, while superoxide in atherosclerotic lesions is increased due to increased NAD(P)H oxidase activity, the applicant's preliminary data suggest that mechanisms contributing to increased superoxide in stenotic valves are fundamentally different, and are likely due to reductions in superoxide dismutase (SOD) enzyme activity and uncoupling of nitric oxide synthase. We will use echocardiographic and magnetic resonance imaging methods to evaluate the changes in aortic valve function in hypercholesterolemic mice over time, and confocal microscopy and laser capture microdissection to examine molecular mechanisms underlying these changes. We propose two main goals: 1) to examine the effects of mitochondria-derived oxidative stress on the progression of AVS using hyperlipidemic MnSOD-deficient and hyperlipidemic MnSOD-overexpressing mice. 2) to determine the role of nitric oxide synthase (NOS) cofactor depletion and the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) on oxidative stress in normal and stenotic human valves ex vivo. We will also examine the role of DDAH1 (an enzyme involved in ADMA degradation) in the progression of AVS using hyperlipidemic DDAH1-deficient and hyperlipidemic DDAH1-overexpressing mice. Collectively, these studies will lend novel insights into the pathophysiology of AVS as well as the effects of treatment of hypercholesterolemia, and thus will lead to new approaches to prevent and treat AVS.

主动脉瓣置换术是有症状的钙化性主动脉瓣狭窄 (AVS) 患者的主要治疗方法，也是世界范围内最常见的瓣膜外科手术。狭窄瓣膜在组织学上与动脉粥样硬化病变相似，申请人的实验室已显示动脉粥样硬化病变中的超氧化物和高胆固醇血症小鼠的狭窄瓣膜中的超氧化物显着增加(Idlr-/-/ApoBI00/100)。然而，虽然动脉粥样硬化病变中的超氧化物由于NAD(P)H氧化酶活性增加而增加，但申请人的初步数据表明，导致狭窄瓣膜中超氧化物增加的机制根本不同，并且可能是由于超氧化物歧化酶(SOD)酶活性的降低和一氧化氮合酶的解偶联所致。我们将使用超声心动图和磁共振成像方法来评估主动脉瓣功能的变化 随着时间的推移，高胆固醇血症小鼠，并使用共聚焦显微镜和激光捕获显微切割来检查这些变化背后的分子机制。我们提出两个主要目标：1）使用高脂血症 MnSOD 缺乏和高脂血症 MnSOD 过度表达小鼠来检查线粒体源性氧化应激对 AVS 进展的影响。 2) 确定一氧化氮合酶 (NOS) 辅因子消耗和内源性 NOS 抑制剂不对称二甲基精氨酸 (ADMA) 对正常和狭窄人瓣膜离体氧化应激的作用。我们还将使用高脂血症 DDAH1 缺陷和高脂血症 DDAH1 过度表达小鼠来研究 DDAH1（一种参与 ADMA 降解的酶）在 AVS 进展中的作用。总的来说，这些研究将为 AVS 的病理生理学以及高胆固醇血症的治疗效果提供新的见解，从而带来预防和治疗 AVS 的新方法。