Oxidative stress and aortic valve disease

氧化应激与主动脉瓣疾病

基本信息

批准号：
7925134
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
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7925134
关键词：
Animals Aortic Valve Stenosis Arterial Fatty Streak Atherosclerosis Award Biological Models Biology Blood Vessels Breeding Cell Culture Techniques Clinic Confocal Microscopy Core Facility Data Enzymes Floor Functional disorder Future Goals Grant Histologic Human Institution Laboratories Lead Magnetic Resonance Imaging Mentorship Methods Mitochondria Molecular Mouse Strains Mus N,N-dimethylarginine Nitric Oxide Synthase Operative Surgical Procedures Oxidases Oxidative Stress Patients Phase Resources Role Superoxide Dismutase Superoxides Testing Thrombosis Time TimeLine aortic valve aortic valve disorder aortic valve replacement base calcification cofactor enzyme activity hypercholesterolemia imaging modality in vitro Model in vivo inhibitor/antagonist insight instrument interstitial cell laser capture microdissection meetings novel novel strategies overexpression prevent treatment effect

项目摘要

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.

主动脉瓣的替代是对有症状，钙化主动脉瓣狭窄（AVS）患者的主要治疗方法，是全球执行的最常见瓣膜外科手术。狭窄的瓣膜在组织学上与动脉粥样硬化病变相似，申请人的实验室在动脉粥样硬化病变中的超氧化物中表现出明显的NCREAS和高胆固醇小鼠的狭窄瓣膜{IDLR - / - / - / - /apobioo/100）。然而，尽管由于NAD（P）H氧化酶活性的增加而增加了动脉粥样硬化病变中的超氧化物，但申请人的初步数据表明，导致狭窄瓣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）Enzyme Active and Nitric oxasase and nitric oxines的超氧化酶（SOD）Enzyme Active and nitric oxIDES的降低所致。我们将使用超声心动图和磁共振成像方法评估主动脉瓣功能的变化高胆固醇小鼠随着时间的流逝，共聚焦显微镜和激光捕获显微解剖，以检查这些变化的分子机制。我们提出了两个主要目标：1）检查使用高脂症状MNSOD缺陷和高脂症MNSOD过表达的小鼠使用线粒体衍生的氧化应激对AVS进展的影响。 2）确定一氧化氮合酶（NOS）辅因子耗竭和内源性NOS抑制剂不对称二甲基精氨酸（ADMA）对正常和狭窄的人瓣中氧化应激的作用。我们还将使用高脂症状DDAH1缺陷和高脂症状DDAH1过表达的小鼠来研究DDAH1（与ADMA降解有关的酶）在AVS进展中的作用。总的来说，这些研究将为AV的病理生理以及高胆固醇血症治疗的影响提供新的见解，从而导致预防和治疗AV的新方法。