MECHANISMS OF DYSLIPIDEMIA IN CARDIAC MUSCLE PRIOR TO ONSET OF ATHEROSCLEROSIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。肥胖在美国已经达到了流行病的程度，并且与心血管疾病的发病率增加有关。在肥胖中，胆固醇、游离脂肪酸和肿瘤坏死因子α (tnf - α)的水平升高，并导致血脂异常心肌病的风险增加。我们假设胆固醇、棕榈酸酯和tnf - α会通过改变细胞膜脂质组成和激活细胞内信号级联导致收缩功能减弱来诱导心脏收缩功能障碍。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小鼠（ob/ob），以区分胆固醇和脂质毒性介导的影响与动脉粥样硬化介导的影响，以及血脂异常小鼠体内模型中胰岛素抵抗引起的并发症。细胞膜中的高胆固醇含量会导致细胞膜渗漏，并降低主要离子泵的活性。这导致细胞内钠和钙的积累扰乱离子稳态，并导致收缩功能障碍。我们假设肌细胞的能量状态受到ATP利用增加以维持离子稳态的影响。重要的问题是渗漏膜在多大程度上和在什么时间内引起心肌细胞离子稳态和能量代谢的紊乱，以及这是否会导致心脏能量供需的不匹配。预防膜脂稳态紊乱是预防或延缓与肥胖相关的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 incident 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 cardiac contractile dysfunction via changes in the lipid composition of the membrane, and 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 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.