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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 肥胖在美国已经达到流行病的程度，并与心血管疾病发病率的增加有关。在肥胖症中，胆固醇、游离脂肪酸和肿瘤坏死因子α（TNF-α）的水平升高，并导致血脂异常性心肌病的风险增加。我们假设胆固醇、棕榈酸盐和TNF-α将诱导：（i）通过膜脂质组成的变化引起心脏收缩功能障碍，和（ii）激活导致收缩性能降低的细胞内信号级联。我们将比较胆固醇喂养和高脂肪喂养的小鼠与年轻的血脂异常（ob/ob）小鼠，以区分胆固醇和脂质毒性介导的影响动脉粥样硬化介导的影响，并确定由于胰岛素抵抗的发病在血脂异常的体内小鼠模型的并发症。膜中的高胆固醇含量导致它们变得渗漏，并且另外降低主要离子泵的活性。这导致离子稳态紊乱，细胞内钠和钙积累，并导致收缩功能障碍。我们推测，心肌细胞的能量状态受到ATP利用率增加的影响，以维持离子稳态。重要的问题是，在何种程度上，在什么时间过程中，膜渗漏导致心肌细胞的离子稳态和能量代谢紊乱，以及这是否会导致心脏能量供应和需求的不匹配。预防膜脂稳态紊乱是预防或延缓肥胖相关心血管并发症的潜在治疗方法。