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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 肥胖症已达到美国的流行维度，并与心血管疾病的发病率增加有关。在肥胖症中，胆固醇，游离脂肪酸和肿瘤坏死因子α（TNF-Alpha）的水平升高，并有助于增加症状性心肌病的风险。我们假设胆固醇，棕榈酸酯和TNF-α将诱导：（i）通过膜的脂质组成的变化，心脏收缩功能障碍，以及（ii）细胞内信号传导级联激活，导致收缩性降低。我们将与年轻的血脂症（OB/OB）小鼠进行比较，以区分胆固醇和脂质毒性介导的作用与动脉粥样硬化介导的作用，并确定由于体内胰岛素耐药性而引起的并发症。膜中的高胆固醇含量会导致它们泄漏，此外，降低了主要离子泵的活性。这会导致因钠和钙的细胞内积累而受到干扰的离子稳态，并导致收缩功能障碍。我们假设肌细胞的能量状态受ATP利用来维持离子稳态的影响。重要的问题是渗漏的膜在多大程度上和在什么程度上会导致心肌肌细胞的离子稳态和能量代谢的干扰，以及这是否会导致心脏能源供应和需求的不匹配。预防膜脂质稳态的障碍是预防或延迟与肥胖相关的心血管并发症的潜在治疗方法。