Ang II, RAGE and Oxidative Stress in Type II Diabetic Coronary Artery Remodeling

II 型糖尿病冠状动脉重塑中的 Ang II、RAGE 和氧化应激

基本信息

批准号：
7848266
负责人：
Pamela A Lucchesi
金额：
$ 43.57万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-01-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7848266
关键词：
Acetylcysteine Address Agonist Antioxidants Arteries Attenuated Biochemical Blood Vessels Blood flow Caliber Cardiovascular system Chronic Coronary Coronary Arteriosclerosis Coronary artery Data Diabetes Mellitus Endothelium Exercise Exertion Exhibits Extracellular Matrix Functional disorder Generations Growth Heart Hyperglycemia Knock-out Lead Mechanics Mesentery Mitochondria Molecular Molecular Target Mus Myocardial Infarction Myocardial perfusion NADP NADPH Oxidase Non-Insulin-Dependent Diabetes Mellitus Organ Oxidation-Reduction Oxidative Stress Pathway interactions Pattern Phenotype Phosphotransferases Production Property Proto-Oncogene Proteins c-akt Regulation Relative (related person)Renin-Angiotensin System Resistance Role Signal Pathway Signal Transduction Signaling Molecule Smooth Muscle Myocytes Stroke Structure Therapeutic Intervention Transgenic Organisms Vascular remodeling Vasodilation acetovanillone aminoguanidine arterial stiffness cell growth crosslink db/db mouse diabetic glycation in vivo inhibitor/antagonist insight mimetics mouse model prevent public health relevance receptor receptor for advanced glycation endproducts response tempol

项目摘要

DESCRIPTION (provided by applicant): Type 2 diabetes causes cardiovascular complications including coronary artery disease. Little is known about the effects of diabetes on structural remodeling of coronary arteries. Alterations in coronary artery lumen diameter and stiffness result in reduced coronary flow reserve. Both the composition of the extracellular matrix (ECM) and vascular smooth muscle cell (VSMC) growth are key determinants of artery remodeling. Chronic hyperglycemia-induced formation of advanced glycation products (AGEs) and activation of the renin-angiotensin system (RAS) are increased in Type 2 diabetes and are related to increased oxidative stress. Preliminary data using the db/db mouse model of Type 2 diabetes indicate increased coronary artery oxidative stress, AGE accumulation and expression of AGE receptors (RAGE), AT1 receptors (AT1R) and the Nox-1 subunit of the NADPH oxidase. These molecular changes preceded increased coronary artery stiffness and inward structural remodeling. Pretreatment with the NADPH oxidase inhibitor apocynin or the AT1R blocker candesartan reduced inward vessel remodeling. Compared to Db/db controls, both coronary arteries and coronary VSMC from db/db mice have increased activation of kinase signaling cascades that are crucial for vessel remodeling. Moreover, db/db coronary VSMC exhibit increased proliferative responses to Ang II and AGE/RAGE. The overall hypothesis is that increased Ang II- and AGE-dependent oxidative stress in Type 2 diabetes alters coronary artery VSMC phenotype to increase proliferation and ECM production, leading to structural remodeling and increased stiffness. Aim 1 will utilize pharmacological inhibitors and NADPH deficient mice to establish the relative contribution of the NADPH oxidase vs. mitochondrial-induced ROS generation in diabetes-induced coronary artery remodeling. Studies in Aim 2 will use molecular and transgenic disruption of the AGE/RAGE pathway to define the molecular mechanisms by which AGE/RAGE regulate coronary artery remodeling and stiffness. Studies in Aim 3 will define the molecular interplay between RAS, AGE/RAGE, and oxidative stress in the regulation of coronary artery remodeling. A comprehensive biochemical and transgenic approach will be used to define the signaling pathways that regulate VSMC growth and ECM accumulation. PUBLIC HEALTH RELEVANCE: The proposed studies will identify unique molecular targets that contribute to Type 2 diabetes- induced coronary artery disease. Increased stiffness of coronary arteries, along with narrowing of the lumen, causes decreased blood flow to the heart during exercise and exertion, leading to myocardial infarction.

描述（由申请人提供）：2型糖尿病会导致心血管并发症，包括冠状动脉疾病。关于糖尿病对冠状动脉结构重塑的影响知之甚少。冠状动脉管腔直径和刚度的改变导致冠状动脉流量减少。细胞外基质（ECM）和血管平滑肌细胞（VSMC）生长的组成都是动脉重塑的关键决定因素。慢性高血糖诱导的晚期糖基化产物（年龄）的形成和肾素 - 血管紧张素系统（RAS）的激活在2型糖尿病中增加，并且与氧化应激增加有关。使用2型糖尿病的DB/DB小鼠模型的初步数据表明，冠状动脉氧化应激，年龄受体的年龄积累和年龄受体的表达（RAGE），AT1受体（AT1R）和NADPH氧化酶的NOX-1亚基。这些分子变化之前是冠状动脉刚度增加和内向结构重塑。用NADPH氧化酶抑制剂的apocynin或AT1R阻滞剂Candesartan预处理可减少内部血管重塑。与DB/DB对照相比，DB/DB小鼠的冠状动脉和冠状动脉VSMC都增加了激酶信号级联的激活，这对于血管重塑至关重要。此外，DB/DB冠状动脉VSMC对ANG II和年龄/愤怒的增殖反应增加。总体假设是，在2型糖尿病中，ANG II和年龄依赖性氧化应激增加会改变冠状动脉VSMC表型，以增加增殖和ECM产生，从而导致结构重塑和刚度增加。 AIM 1将利用药理学抑制剂和NADPH缺乏小鼠来建立NADPH氧化酶与线粒体诱导的ROS在糖尿病诱导的冠状动脉重塑中的相对贡献。 AIM 2中的研究将使用年龄/愤怒途径的分子和转基因破坏来定义分子机制，通过这种机制，年龄/愤怒调节冠状动脉重塑和僵硬。 AIM 3中的研究将定义RAS，年龄/愤怒和氧化应激之间的分子相互作用，以调节冠状动脉重塑。全面的生化和转基因方法将用于定义调节VSMC生长和ECM积累的信号通路。公共卫生相关性：拟议的研究将确定有助于2型糖尿病引起的冠状动脉疾病的独特分子靶标。冠状动脉动脉的刚度增加，以及管腔的变窄，导致运动和劳累期间血液流向心脏，导致心肌梗塞。