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Vascular Mechanisms in Homocysteinemia and Atherosclerosis

同型半胱氨酸血症和动脉粥样硬化的血管机制

基本信息

批准号：
8232154
负责人：
Steven R Lentz
金额：
$ 35.71万
依托单位：
UNIVERSITY OF IOWA
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：
2009-05-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8232154
关键词：
Adipocytes Age Antioxidants Atherosclerosis Blood Vessels Cardiovascular Diseases Catalytic Domain Cause of Death Cell Death Cellular Stress Cellular Stress Response Clinical Cohort Studies Data Development Dominant-Negative Mutation Down-Regulation Endoplasmic Reticulum Endothelial Cells Endothelium Event Folic Acid Functional disorder Funding GRP78 gene Genes Goals Health Health Expenditures Homocysteine Homocystine Hyperhomocysteinemia Individual Lead Mediating Mediator of activation protein Meta-Analysis Metabolism Methionine Methionine Metabolism Pathway Modeling Molecular Molecular Chaperones Morbidity - disease rate Mus Muscle Mutation Myocardial Infarction NADP NADPH Oxidase Nuclear Receptors Oxidative Stress PPAR gamma Pathway interactions Patients Plasma Play Predisposition Prevention Primary Prevention Randomized Risk Risk Factors Role Secondary Prevention Skeletal Muscle Smooth Muscle Myocytes Source Stroke Supplementation T-Lymphocyte Testing Thrombosis Tissues Uncertainty Vasomotor Venous Venous Thrombosis Vitamin B Complex Work cardiovascular risk factor endoplasmic reticulum stress experience glucose-regulated proteins high risk hypercholesterolemia neointima formation overexpression population based prevent protective effect secondary outcome transcription factor

项目摘要

DESCRIPTION (provided by applicant): Hyperhomocysteinemia and hypercholesterolemia are common cardiovascular risk factors that often occur together in patients with vascular thrombotic events. A better understanding of the pathophysiological pathways by which hyperhomocysteinemia and hypercholesterolemia, alone or in combination, predispose to vascular dysfunction is needed to develop more selective targets for the prevention and treatment of vascular events. During the previous funding period, this project investigated mechanisms of vascular dysfunction in murine models of hyperhomocysteinemia. We now propose to focus on interactions between hyperhomocysteinemia and hypercholesterolemia that lead to vascular dysfunction, neointima formation, and thrombosis. Our preliminary data suggest that hyperhomocysteinemia and hypercholesterolemia induce cellular stress responses (oxidative stress and endoplasmic reticulum (ER) stress) through common mechanisms, including the activation of NADPH oxidase and T cell death-associated gene 51 (TDAG51). The overall goal of this project is to define the molecular mechanisms by which hyperhomocysteinemia and hypercholesterolemia, alone or in combination, lead to vascular dysfunction and thrombosis. Our specific objectives are to determine the mechanistic roles of NADPH oxidase, which we hypothesize to be a major source of oxidative stress, and TDAG51, which we hypothesize to be a major mediator of ER stress. We will use genetically altered mice to probe mechanisms that lead to, and protect against vasomotor dysfunction, neointima formation, and thrombosis induced by hyperhomocysteinemia and/or hypercholesterolemia. In Aim 1, we will test the hypothesis that hyperhomocysteinemia and hypercholesterolemia induce cellular oxidative stress, vascular dysfunction, increased neointima formation, and enhanced susceptibility to thrombosis through a mechanism involving vascular NADPH oxidase. We propose to test this hypothesis by determining the vascular phenotypic effects of altered expression of the NADPH catalytic subunits Nox1 and Nox4, as well as peroxisome proliferator-activated receptor gamma (PPAR3), in vascular smooth muscle cells (SMC) and mice. In Aim 2, we will test the hypothesis that hyperhomocysteinemia and hypercholesterolemia induce ER stress, leading to TDAG51-mediated vasomotor dysfunction, increased neointimal formation, and enhanced susceptibility to thrombosis. We propose to test this hypothesis by determining the vascular phenotypic effects of altered expression of TDAG51 and glucose-regulated protein 78 (GRP78; an ER chaperone that protects from ER stress) in endothelial cells (EC), SMC, and mice. We also propose to ascertain the role of PPAR3 downregulation in mediating the vascular effects of ER stress and TDAG51 by determining the vascular phenotypic effects of tissue-specific overexpression of dominant-negative PPAR3 in endothelium or vascular muscle. Thus, we propose to use these models and approaches to define the roles of two fundamental cellular stress pathways, each of which has the potential to be targeted therapeutically. PUBLIC HEALTH RELEVANCE: Cardiovascular disease and its complications are major causes of death, morbidity, and health care expenditures. Hyperhomocysteinemia and hypercholesterolemia are common cardiovascular risk factors that often occur together in patients with clinical vascular events. The goals of this project are to define the molecular mechanisms by which hyperhomocysteinemia and hypercholesterolemia, alone or in combination, lead to adverse vascular events, and to identify new targets for therapy.

描述（由申请人提供）：高同型半胱氨酸血症和高胆固醇血症是常见的心血管危险因素，经常同时发生在患有血管血栓事件的患者中。需要更好地了解高同型半胱氨酸血症和高胆固醇血症单独或组合导致血管功能障碍的病理生理学途径，以开发更有选择性的目标来预防和治疗血管事件。在之前的资助期间，该项目研究了高同型半胱氨酸血症小鼠模型中血管功能障碍的机制。我们现在建议重点关注高同型半胱氨酸血症和高胆固醇血症之间的相互作用，这些相互作用会导致血管功能障碍、新内膜形成和血栓形成。我们的初步数据表明，高同型半胱氨酸血症和高胆固醇血症通过常见机制诱导细胞应激反应（氧化应激和内质网（ER）应激），包括激活NADPH氧化酶和T细胞死亡相关基因51（TDAG51）。该项目的总体目标是确定高同型半胱氨酸血症和高胆固醇血症单独或联合导致血管功能障碍和血栓形成的分子机制。我们的具体目标是确定 NADPH 氧化酶（我们假设其是氧化应激的主要来源）和 TDAG51（我们假设其是 ER 应激的主要介质）的机制作用。我们将使用基因改造的小鼠来探索导致血管舒缩功能障碍、新内膜形成以及高同型半胱氨酸血症和/或高胆固醇血症引起的血栓形成的机制，并防止这些机制。在目标 1 中，我们将检验以下假设：高同型半胱氨酸血症和高胆固醇血症通过涉及血管 NADPH 氧化酶的机制诱导细胞氧化应激、血管功能障碍、新内膜形成增加以及血栓形成的易感性增强。我们建议通过确定 NADPH 催化亚基 Nox1 和 Nox4 以及过氧化物酶体增殖物激活受体 γ (PPAR3) 表达改变对血管平滑肌细胞 (SMC) 和小鼠的血管表型影响来检验这一假设。在目标 2 中，我们将检验以下假设：高同型半胱氨酸血症和高胆固醇血症诱导 ER 应激，导致 TDAG51 介导的血管舒缩功能障碍、增加新内膜形成并增强血栓形成的易感性。我们建议通过确定内皮细胞 (EC)、SMC 和小鼠中 TDAG51 和葡萄糖调节蛋白 78（GRP78；一种防止 ER 应激的 ER 伴侣）表达改变对血管表型的影响来检验这一假设。我们还建议通过确定内皮或血管肌肉中显性失活 PPAR3 的组织特异性过度表达的血管表型效应来确定 PPAR3 下调在介导 ER 应激和 TDAG51 的血管效应中的作用。因此，我们建议使用这些模型和方法来定义两种基本细胞应激途径的作用，每种途径都有可能成为治疗目标。公共卫生相关性：心血管疾病及其并发症是死亡、发病和医疗保健支出的主要原因。高同型半胱氨酸血症和高胆固醇血症是常见的心血管危险因素，经常同时发生在有临床血管事件的患者中。该项目的目标是确定高同型半胱氨酸血症和高胆固醇血症单独或联合导致不良血管事件的分子机制，并确定新的治疗靶点。