MECHANISMS OF DYSLIPIDEMIA IN CARDIAC MUSCLE PRIOR TO ONSET OF ATHEROSCLEROSIS

动脉粥样硬化发生前心肌血脂异常的机制

• 批准号: 7959656
• 负责人: ILKA M PINZ
• 金额: $ 26.32万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959656
• 关键词: Affect; Atherosclerosis; Biology; Blood Vessels; Calcium; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Centers of Research Excellence; Cholesterol; Computer Retrieval of Information on Scientific Projects Database; Dimensions; Dyslipidemias; Energy Metabolism; Energy Supply; Epidemic; Fatty acid glycerol esters; Functional disorder; Funding; Grant; Homeostasis; Incidence; Institution; Insulin Resistance; Ion Pumps; Ions; Lead; Leptin; Lipids; Mediating; Membrane; Membrane Lipids; Mus; Muscle Cells; Myocardium; Nonesterified Fatty Acids; Obesity; Palmitates; Performance; Prevention; Research; Research Personnel; Resources; Risk; Signal Transduction; Sodium; Source; Therapeutic; Time; Toxic effect; Tumor Necrosis Factor-alpha; United States; United States National Institutes of Health; feeding; human TNF protein; in vivo; mouse model; prevent

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Obesity has reached epidemic dimensions in the United States and correlates with the increased incidence of cardiovascular disease. In obesity, the levels of cholesterol, free fatty acids, and tumor necrosis factor alpha (TNF-alpha) are elevated, and contribute to the increased risk of dyslipidemic cardiomyopathy. We hypothesize that cholesterol, palmitate, and TNF-alpha will induce: (i) cardiac contractile dysfunction via changes in the lipid composition of the membrane, and (ii) activation of intracellular signaling cascades that lead to diminished contractile performance. We will compare cholesterol fed and high fat fed mice with young dyslipidemic (ob/ob) mice, to distinguish cholesterol and lipid toxicity-mediated effects from effects mediated by atherosclerosis, and determine complications due to the onset of insulin resistance in the dyslipidemic in vivo mouse models. High cholesterol content in membranes causes them to become leaky, and in addition decreases the activity of major ion pumps. This leads to disturbed ion homeostasis with intracellular accumulation of sodium and calcium, and contributes to contractile dysfunction. We hypothesize that the energetic state of the myocyte is affected by increased ATP utilization to maintain ion homeostasis. Important questions are to what extent and in what time course leaky membranes cause disturbances in the ion homeostasis and energy metabolism of cardiac myocytes, and whether this causes a mismatch in cardiac energy supply and demand. The prevention of disturbances in membrane lipid homeostasis is a potential therapeutic approach to prevent or delay the cardiovascular complications associated with obesity.

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