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Novel mechanistic pathways of cardiovascular disease in obesity

肥胖症心血管疾病的新机制途径

基本信息

批准号：
9467595
负责人：
David J Fulton
金额：
$ 55.63万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9467595
关键词：
Age Animals Binding Biology Blood Pressure Blood Vessels Body Weight decreased Carbohydrates Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Clinic Clinical Data Defect Diabetes Mellitus Endothelium Exercise Experimental Models Extracellular Space Family member Functional disorder GDF8 gene Galactosides Galectin 3 Gene Deletion Gene Expression Genes Genetic Glucose Goals Growth Health Human Impairment In Vitro Injury Insulin Resistance Intervention Intracellular Space Knockout Mice Lectin Light Link Lipids Measures Mediating Mediator of activation protein Metabolic Metabolic Control Metabolic Diseases Metabolic dysfunction Metabolism Methods Molecular Morbidity - disease rate Muscle Muscular Atrophy Mutation NADPH Oxidase 1 Obese Mice Obesity Outcome Oxidants Pathway interactions Patients Performance Pharmaceutical Preparations Physiological Plasma Population Production Proteins Reactive Oxygen Species Regulation Research Role Secondary to Signal Transduction Skeletal Muscle Stimulus Stress Superoxides Techniques Testing Therapeutic Transforming Growth Factor beta Translations Up-Regulation Vascular Diseases Vasodilation Weight cardiometabolism cardiovascular health cardiovascular risk factor db/db mouse experimental study glucose disposal glucose tolerance heart function hemodynamics improved in vivo in vivo evaluation insulin signaling mortality muscle form muscle physiology new therapeutic target novel overexpression oxidant stress public health relevance response targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Morbidity and mortality secondary to cardiovascular disease is the major health problem in obese patients. Obese patients are burdened with an array of metabolic dysfunctions associated with excess weight which drive the cardiovascular disease evident in this population. While this correlation is well-established, mechanistic links that could be exploited therapeutically are largely lacking. In preliminary studies for this proposal, we have made two major observations that shed significant new light on this issue. The first is that loss of metabolic control in skeletal muscle appears to be the key trigger for vascular injury in obesity. Correction of rapid glucose disposal by deletion of genes that limit insulin signaling or muscle growth appear to restore endothelial function in vitro and may underpin cardiovascular defects systemically. The second observation is the NADPH Oxidase 1 (Nox1) is a major culprit in vascular defects in obesity. Nox1 is overexpressed in large and small vessels from obese mice and appears driven by glucose excess, potentially via upregulation of galectin-3. In the current proposal, we will rigorously test these concepts in three aims. The firs aim will use state-of-the-art molecular techniques in vitro to determine the signaling mechanisms by which changes in the plasma milieu, specifically glucose, induce changes in Nox expression and superoxide production with specific emphasis on the role of galectin-3. The second aim will generate novel Nox1 and Galectin-3 KO mice on a genetically obese background to test the hypothesis that these two oxidant pathways contribute to vascular dysfunction in vitro with a specific emphasis on determining whether improving metabolism by increasing muscle mass obviates pro oxidant pathways. The third aim will pursue these concepts in vivo, testing whether increased muscle mass or blocking the Nox1/Galectin-3 signaling axis improves cardiovascular outcomes like blood pressure and vascular adaptions to hemodynamic stress. Taken together, these studies will provide new information on the mechanisms, mediators and physiologic impact of obesity-induced metabolic dysfunction. Successful completion of these aims may identify new targets to aid in the treatment of some the most pressing clinical outcomes of obesity.