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Oxidative stress and aortic valve disease

氧化应激与主动脉瓣疾病

基本信息

批准号：
7449957
负责人：
Jordan D Miller
金额：
$ 10.72万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-24 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7449957
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)Data Development Disease Disease regression Effectiveness Enzymes Exhibits Functional disorder Genetic Goals Grant Histologic Human Hypertension Inflammation Jordan Laboratories Laser Microscopy Lead Lesion Link Lipids Magnetic Resonance Imaging Manganese Superoxide Dismutase Mentors Methods Mitochondria Molecular Mus N,N-dimethylarginine NAD(P)H oxidase Nitric Oxide Nitric Oxide Synthase Nodule Operative Surgical Procedures Osteoblasts Osteoclasts Oxidative Stress Pathogenesis Patients Phase Plasma Play Population Process Production Protein Overexpression Rate Reactive Oxygen Species Research Personnel Risk Factors Role Smoking Superoxide Dismutase Superoxides Time United States Ursidae Family aortic valve aortic valve disorder base blood lipid cofactor dimethylargininase enzyme activity human NOS3 protein hypercholesterolemia inhibitor/antagonist insight laser capture microdissection male novel novel strategies prevent programs retinal rods sex size tetrahydrobiopterin treatment effect

项目摘要

DESCRIPTION (provided by applicant): 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 (> 250,000 performed annually). Stenotic valves are histologically similar to atherosclerotic lesions, and the applicant's laboratory has shown significant increases in superoxide in atherosclerotic lesions and stenotic valves in hypercholesterolemic mice (ldlr-/-/ApoB100/100). 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. The applicant has developed 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. The applicant proposes two main goals: 1) to examine the effects of treating hypercholesterolemia on the progression of aortic valve disease, and 2) to identify molecular mechanisms contributing to the pathogenesis of aortic valve disease. During the K99/Mentored phase of the grant, the applicant will examine the effects of aggressive lipid lowering on the progression of valve disease in hyperlipidemic mice, using a "genetic switch" to normalize cholesterol levels (using Ldlr-/-/Apob100/100/ Mttpfl/fl/Mx1Cre+/+ mice, also called "Reversa" mice). During the R00/lndependent phase of the grant, the applicant will examine mechanisms that predispose to the development of aortic valve stenosis. In the first portion of the R00 phase, the applicant will determine the role of mitochondria-derived oxidative stress on the progression of AVS using hyperlipidemic MnSOD-deficient and hyperlipidemic MnSOD-overexpressing mice. In the second portion of the ROD phase, the applicant will 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. The applicant 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.

描述（由申请人提供）：主动脉瓣置换术是症状性钙化性主动脉瓣狭窄（AVS）患者的主要治疗方法，也是最常见的瓣膜外科手术（每年> 250，000例）。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高胆固醇血症小鼠（ldlr-/-/ApoB 100/100）动脉粥样硬化病变和狭窄瓣膜中的超氧化物显著增加。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）酶活性降低和一氧化氮合酶解偶联。申请人开发了超声心动图和磁共振成像方法，以评价高胆固醇血症小鼠主动脉瓣功能随时间的变化，并开发了共聚焦显微镜和激光捕获显微切割，以检查这些变化的分子机制。申请人提出了两个主要目标：1）检查治疗高胆固醇血症对主动脉瓣疾病进展的影响，以及2）确定促成主动脉瓣疾病发病机制的分子机制。在资助的K99/Mentored阶段，申请人将检查积极降脂对高脂血症小鼠瓣膜疾病进展的影响，使用“遗传开关”使胆固醇水平正常化（使用Ldlr-/-/Apob 100/100/ Mttpfl/fl/Mx 1Cre +/+小鼠，也称为“逆转”小鼠）。在R 00/独立资助阶段，申请人将检查易患主动脉瓣狭窄的机制。在R 00阶段的第一部分中，申请人将使用高血MnSOD缺陷和高血MnSOD过表达小鼠确定动脉源性氧化应激对AVS进展的作用。在ROD阶段的第二部分，申请人将确定一氧化氮合酶（NOS）辅因子耗竭和内源性NOS抑制剂不对称二甲基精氨酸（ADMA）对离体正常和狭窄人体瓣膜中氧化应激的作用。申请人还将使用高脂血症性DDAH 1缺陷和高脂血症性DDAH 1过表达小鼠检查DDAH 1（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，从而将导致预防和治疗AVS的新方法。