The role of Myocardial Substrate Metabolism in Heart Failure

心肌底物代谢在心力衰竭中的作用

基本信息

批准号：
8495281
负责人：
Mogammad Faadiel Essop
金额：
$ 5.08万
依托单位：
STELLENBOSCH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8495281
关键词：
Acceleration Acetylglucosamine Acquired Immunodeficiency Syndrome Address Affect Africa Age Animals Apoptosis Apoptotic BCL2 gene Biochemical Carbohydrates Cardiac Cardiac Myocytes Cardiovascular Diseases Cause of Death Cell Death Cell physiology Cells Cellular biology Central obesity Chronic Chronic Disease Collaborations Critiques Data Developed Countries Developing Countries Development Diet Dietary intake Dimerization Dyslipidemias Epidemiologic Studies Europe Fatty acid glycerol esters Food Food Processing Foundations Functional disorder Funding Glucose Glycemic Index Glycolysis Grant HIV Heart Heart failure Hexosamines Homologous Gene Hyperglycemia Hypertension In Vitro Incidence Insulin Insulin Resistance Intake Journals Knowledge Laboratories Life Style Light Link Macronutrients Nutrition Mediating Metabolic Metabolic syndrome Metabolism Mitochondria Molecular Biology Mus Myocardial NADP Nonesterified Fatty Acids Nutritional Obesity Oxidative Stress Oxidoreductase Pathology Pathway interactions Pentosephosphate Pathway Pentosephosphates Phenotype Physical activity Physiological Plasma Play Post-Translational Protein Processing Prevalence Process Production Proteins Protocols documentation Public Health Rattus Reporting Research Research Project Grants Risk Risk Factors Role Science Serine Signal Transduction South Africa Starch Study Section Threonine Tissues United States National Institutes of Health Universities Urbanization Woman Work World Health Organization base diabetic cardiomyopathy editorial glucose metabolism glucose uptake in vivo interest men nutrition oxidation parent grant pressure programs sensor stem sugar

项目摘要

DESCRIPTION (provided by applicant): This research will be done primarily in South Africa at Stellenbosch University by Dr. M. Faadiel Essop, as a (collaborative) extension of Dr. Stanley's NIH Grant No. P01 HL074237 (funded 8/15/2009 to 7/30/2014). This collaborative research project stems from Drs. Stanley and Essop's mutual interest in the role of myocardial substrate metabolism in heart failure. Dr. Essop is based at the Dept. Physiological Sciences at Stellenbosch University (South Africa), and has established a productive collaboration with Dr. Stanley. There has been a marked increase for the incidence of cardiovascular disease (CVD) in Africa, and recent data suggest that the dramatic surge in CVD rates are largely due to lifestyle changes. Epidemiological studies from the US and Europe recently showed that high intake of carbohydrates with a high glycemic index (e.g. sugars and refined starches) are a strong independent predictor of CVD, and public health efforts are now focused on removing "empty carbohydrates" from the diet. These findings have led Dr. Essop to study the link between suboptimal nutrition and the increased CVD. The foundations for this collaboration are the limited knowledge regarding the effects of macronutrient intake on cardiomyocyte function and the observation by Dr. Essop that increased flux through the hexosamine biosynthetic pathway plays a crucial role in hyperglycemia- induced myocardial cell death. This project will combine Dr. Essop's expertise in molecular and cell biology with Dr. Stanley's expertise in nutrition and the pathophysiology of heart failure. Extensive cell-based and biochemical studies will be performed in Stellenbosch, while in vivo functional studies will be performed in Dr. Stanley's laboratory. The general hypothesis is that oxidative stress resulting from intake of high glycemic foods activates the HBP leading to increased O-GlcNAcylation of cardiac apoptotic proteins and elevated myocardial apoptosis, thereby accelerating the development and progression to heart failure. Specifically, we propose that there is increased BAD O-GlcNAcylation and BAD-Bcl-2 dimerization, thus accelerating apoptosis. There are two Specific Aims: Aim 1: Evaluate the role of HBP in the acceleration of heart failure with a high sugar diet. Studies will be performed in normal mice and animals subjected to a chronic increase in arterial pressure to induce heart failure, and the dietary glycemic load will be manipulated. The role of ROS production will be assessed. Cardiomyocyte apoptosis will be determined, and the biochemical assessment of HBP and O- GlcNAcylation of apoptotic proteins will be preformed. Aim 2: Assess the effects of hyperglycemia-mediated induction of the HBP on O-GlcNAcylation of apoptotic proteins. Systematic in vitro studies will be performed in isolated cardiac cells to determine the mechanism(s) of hyperglycemia-mediated myocardial apoptosis.

描述（由申请人提供）：这项研究将主要由 M. Faadiel Essop 博士在南非斯泰伦博斯大学完成，作为 Stanley 博士的 NIH 拨款编号 P01 HL074237（资助日期：2009 年 8 月 15 日）的（合作）延伸至 2014 年 7 月 30 日）。这个合作研究项目源于博士。 Stanley 和 Essop 对心肌底物代谢在心力衰竭中的作用感兴趣。埃索普博士在斯泰伦博斯大学（南非）生理科学系工作，并与斯坦利博士建立了富有成效的合作。非洲心血管疾病（CVD）发病率显着上升，最近的数据表明，CVD发病率急剧上升很大程度上是由于生活方式的改变。美国和欧洲的流行病学研究最近表明，大量摄入高血糖指数的碳水化合物（例如糖和精制淀粉）是心血管疾病的强有力的独立预测因素，公共卫生工作现在的重点是从饮食中消除“空碳水化合物” 。这些发现促使埃索普博士研究营养不良与心血管疾病增加之间的联系。这项合作的基础是关于常量营养素摄入对心肌细胞功能影响的有限知识，以及 Essop 博士的观察，即增加己糖胺生物合成途径的通量在高血糖诱导的心肌细胞死亡中起着至关重要的作用。该项目将结合埃索普博士在分子和细胞生物学方面的专业知识与斯坦利博士在营养和心力衰竭病理生理学方面的专业知识。广泛的基于细胞和生物化学的研究将在斯泰伦博斯进行，而体内功能研究将在斯坦利博士的实验室进行。一般假设是，摄入高血糖食物引起的氧化应激会激活 HBP，导致心脏凋亡蛋白的 O-GlcNAc 酰化增加和心肌细胞凋亡增加，从而加速心力衰竭的发展和进展。具体来说，我们提出 BAD O-GlcNAc 酰化和 BAD-Bcl-2 二聚化增加，从而加速细胞凋亡。有两个具体目标：目标 1：评估 HBP 在高糖饮食加速心力衰竭中的作用。研究将在正常小鼠和动脉压慢性升高诱发心力衰竭的动物中进行，并控制饮食血糖负荷。将评估 ROS 产生的作用。将测定心肌细胞凋亡，并对凋亡蛋白的 HBP 和 O-GlcNAc 酰化进行生化评估。目标 2：评估高血糖介导的 HBP 诱导对凋亡蛋白 O-GlcNAc 酰化的影响。将在分离的心肌细胞中进行系统的体外研究，以确定高血糖介导的心肌细胞凋亡的机制。