MECHANISMS OF DYSLIPIDEMIA IN CARDIAC MUSCLE PRIOR TO ONSET OF ATHEROSCLEROSIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 肥胖症在美国已经达到流行的程度，并与心血管疾病发病率的增加相关。肥胖患者的胆固醇、游离脂肪酸和肿瘤坏死因子-α水平升高，从而增加了患血脂异常心肌病的风险。我们假设胆固醇、棕榈酸酯和肿瘤坏死因子-α将导致：(I)心肌收缩功能障碍，通过改变细胞膜的脂质成分，以及(Ii)激活细胞内信号级联反应，导致收缩性能下降。我们将比较喂饲胆固醇和高脂肪的小鼠和年轻的血脂异常(ob/ob)小鼠，以区分胆固醇和脂类毒性介导的效应和动脉粥样硬化介导的效应，并确定体内血脂紊乱小鼠模型中胰岛素抵抗的并发症。膜中胆固醇含量高会导致膜渗漏，此外还会降低主要离子泵的活性。这会导致离子动态平衡紊乱，导致细胞内钠和钙的积累，并导致收缩功能障碍。我们假设，心肌细胞的能量状态是通过增加对ATP的利用来维持离子平衡来影响的。重要的问题是，渗漏的膜在多大程度上和在什么时间过程中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需不匹配。预防膜脂平衡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。

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.