Role of HHcy in diabetic vascular disease

HHcy 在糖尿病血管疾病中的作用

基本信息

批准号：
7848216
负责人：
Hong Wang
金额：
$ 36.41万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7848216
关键词：
5&apos -AMP-activated protein kinase Abbreviations Acetates Acetylcholine Acyl Coenzyme A Analysis of Variance Animal Model Apolipoprotein E Arginine Atherosclerosis Beta Cell Biochemical Blood Vessels CCL2 gene Cardiovascular Diseases Cattle Cell Cycle Cell Proliferation Cholesterol Cholesterol Esters Coronary heart disease Cyclic AMP-Dependent Protein Kinases Cyclic GMP Cystathionine Cysteine Data Diabetes Mellitus Diabetic Angiopathies Diabetic mouse Dilatation - action Doctor of Philosophy Dominant-Negative Mutation Endothelial Cells Endothelium Event Experimental Models Fatty acid glycerol esters Functional disorder Gene Expression Growth High Prevalence Homocysteine Homocystine Human Hydrochloride Salt Hyperglycemia Hyperhomocysteinemia In Vitro Infection Knock-out Knockout Mice Lead Link Low-Density Lipoproteins Mediating Methionine Methylation Methylenetetrahydrofolate reductase (NADPH)Molecular Monocyte Chemoattractant Protein-1 Mus Myocardial Infarction N,N-dimethylarginine NG-Nitroarginine Methyl Ester Natural regeneration Nitric Oxide Nitric Oxide Synthase Non-Insulin-Dependent Diabetes Mellitus Odds Ratio Patients Peroxidases Phosphatidylinositols Phosphorylation Plasma Premature Mortality Protein Isoforms Protein Kinase C Reactive Oxygen Species Regulation Reporting Research Personnel Risk Factors Role S-nitro-N-acetylpenicillamine Serine Signal Transduction Smooth Muscle Myocytes Sterol O-Acyltransferase Streptozocin Subarachnoid Hemorrhage Thin Layer Chromatography Threonine Triglycerides Umbilical vein Western Blotting acetyl-LDL arginine methyl ester base cell growth diabetes mellitus genetics diabetic dimethylargininase human NOS3 protein in vivo in vivo Model inhibitor/antagonist insight mouse model novel therapeutic intervention overexpression phorbol-12-myristate programs research study

项目摘要

DESCRIPTION (provided by applicant): In patients with type II diabetes, cardiovascular disease (CVD) is highly prevalent and a major cause of premature mortality and plasma homocysteine (Hcy) levels are increased by 3-4 folds. Hyperhomocysteinemia (hHcy), elevated plasma concentrations of Hcy, has been established as an independent and significant risk factor for CVD, and has been suggested to be responsible for CVD in diabetes that is not explained by traditional risk factors. However, the role of HHcy in diabetic atherosclerosis has not been studied in experimental model. We have previously proposed that Hcy promotes atherosclerosis by stimulating vascular aortic smooth muscle cell (VSMC) proliferation and by inhibiting endothelial cell (EC) growth, and reported that HHcy accelerated spontaneous atherosclerosis in mice. Recently, we found that Hcy potentiated the diabetic inhibitions on EC growth and eNOS activities in human aortic endothelial cells (HAEC). A PKC inhibitor, GFX, reversed these inhibitions. We hypothesize that Hcy potentiates diabetic endothelium damage and eNOS inactivation via PKC activation, which contributes to high prevalence of atherosclerosis in diabetes. This project will study this hypothesis utilizing three linked specific aims. First, in Aim 1, experiments will evaluate the role and mechanisms of Hcy on endothelial cell growth inhibition in diabetes using in vitro and in vivo models. Second, in Aim 2, studies are proposed to determine the role and mechanism of Hcy in eNOS inactivation and PKC activation. Third, in Aim 3, studies will determine the effect of HHcy on endothelial function and atherosclerosis in animal model of diabetes and atherosclerosis. We believe this project will lead to fundamental new insights into the identification of mechanistic links between Hcy and diabetic atherosclerosis. If we can identify the key events in Hcy-induced atherosclerosis in diabetes, genetic or biochemical approaches to block these steps could lead to new therapeutic approaches

描述（由申请人提供）：在 II 型糖尿病患者中，心血管疾病（CVD）非常普遍，是过早死亡的主要原因，血浆同型半胱氨酸（Hcy）水平增加了 3-4 倍。高同型半胱氨酸血症（hHcy），即血浆 Hcy 浓度升高，已被确定为 CVD 的一个独立且重要的危险因素，并被认为是导致传统危险因素无法解释的糖尿病 CVD 的原因。然而，HHcy 在糖尿病动脉粥样硬化中的作用尚未在实验模型中进行研究。我们之前提出Hcy通过刺激血管主动脉平滑肌细胞（VSMC）增殖和抑制内皮细胞（EC）生长来促进动脉粥样硬化，并报道HHcy加速小鼠自发性动脉粥样硬化。最近，我们发现 Hcy 增强了糖尿病对人主动脉内皮细胞 (HAEC) 内皮细胞生长和 eNOS 活性的抑制作用。 PKC 抑制剂 GFX 可以逆转这些抑制作用。我们假设 Hcy 通过 PKC 激活增强糖尿病内皮损伤和 eNOS 失活，从而导致糖尿病患者动脉粥样硬化的高患病率。该项目将利用三个相关的具体目标来研究这一假设。首先，在目标 1 中，实验将使用体外和体内模型评估 Hcy 对糖尿病内皮细胞生长抑制的作用和机制。其次，在目标 2 中，建议研究确定 Hcy 在 eNOS 失活和 PKC 激活中的作用和机制。第三，在目标 3 中，研究将在糖尿病和动脉粥样硬化动物模型中确定 HHcy 对内皮功能和动脉粥样硬化的影响。我们相信这个项目将为鉴定 Hcy 和糖尿病动脉粥样硬化之间的机制联系带来根本性的新见解。如果我们能够确定糖尿病中 Hcy 诱导的动脉粥样硬化的关键事件，那么阻止这些步骤的遗传或生化方法可能会带来新的治疗方法