Oxidative stress and aortic valve disease

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，也是全球最常见的瓣膜外科手术。狭窄瓣膜在组织学上类似于动脉粥样硬化病变，申请人的实验室显示，在高胆固醇血症小鼠的动脉粥样硬化病变和狭窄瓣膜中，超氧化物显著增加[Idlr-/-/ApoBIOO/100]。然而，尽管动脉粥样硬化病变中的超氧化物由于NAD(P)H氧化酶活性的增加而增加，但申请人的初步数据表明，导致狭窄瓣膜中超氧化物歧化的机制是根本不同的，可能是由于超氧化物歧化酶(SOD)活性的降低和一氧化氮合酶的解偶联。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，以及共聚焦显微镜和激光捕获显微解剖，以检查这些变化背后的分子机制。我们提出了两个主要目标：1)利用高脂血症MnSOD缺陷和高脂血症MnSOD过表达的小鼠，检测线粒体衍生的氧化应激对AVS进展的影响。2)探讨一氧化氮合酶(NOS)辅因子缺失及其内源性一氧化氮合酶抑制剂不对称二甲基精氨酸(ADMA)在体外正常和狭窄瓣膜氧化应激中的作用。我们还将研究DDAH1(一种参与ADMA降解的酶)在高脂血症DDAH1缺陷和高脂血症DDAH1过表达小鼠AVS进展中的作用。总而言之，这些研究将为AVS的病理生理学以及治疗高胆固醇血症的效果提供新的见解，从而将导致预防和治疗AVS的新方法。

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.