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：
8271235
负责人：
Mogammad Faadiel Essop
金额：
$ 5.35万
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 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8271235
关键词：
Acceleration Acetylglucosamine Acquired Immunodeficiency Syndrome Address Affect Africa Age Animals Apoptosis Apoptotic 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Stellenbosch University的南非进行，作为Stanley博士NIH的NIH NIH No. P01 HL074237的（合作）扩展（资助8/15/2009至7/30/2014）。该协作研究项目源于Drs。斯坦利和埃索普对心肌底物代谢在心力衰竭中的作用的共同兴趣。 Essop博士位于斯泰伦博斯大学（南非）的生理科学系，并与Stanley博士建立了富有成效的合作。非洲心血管疾病（CVD）的发生率显着增加，最近的数据表明，CVD率的急剧激增主要是由于生活方式的改变。来自美国和欧洲的流行病学研究最近表明，高血糖指数（例如糖和精制淀粉）的碳水化合物的高摄入量是CVD的强有力的独立预测指标，现在公共卫生的努力集中在去除饮食中的“空碳水化合物”。这些发现导致Essop博士研究了次优营养与CVD增加之间的联系。这种合作的基础是关于大量营养素摄入对心肌细胞功能的影响的有限知识以及Essop博士的观察，通过六胺生物合成途径增加了通量，在高血糖诱导的心肌细胞死亡中起着至关重要的作用。该项目将将Essop博士在分子和细胞生物学方面的专业知识与Stanley博士在营养方面的专业知识以及心力衰竭的病理生理相结合。将在Stellenbosch中进行广泛的基于细胞的和生化研究，而在Stanley博士的实验室将进行体内功能研究。一般的假设是，高血糖食品摄入引起的氧化应激激活了HBP，导致心脏凋亡蛋白的O-葡萄球化增加并升高心肌凋亡，从而加速发育和进展到心脏衰竭。具体而言，我们建议O-Glcnacylation和Bad-Bcl-2二聚化增加，从而加速了凋亡。有两个具体的目的：目标1：评估HBP在高糖饮食中的心力衰竭加速中的作用。将在正常小鼠中进行研究，并在动脉压长期增加动脉压力以诱导心力衰竭的情况下进行研究，并将操纵饮食性血糖负荷。将评估ROS产生的作用。将确定心肌细胞凋亡，并将预先形成凋亡蛋白的HBP和O- Glcnacylation的生化评估。 AIM 2：评估高血糖介导的HBP诱导对凋亡蛋白O-Glcnacylation的影响。系统的体外研究将在分离的心脏细胞中进行，以确定高血糖介导的心肌凋亡的机制。