Effect of SMSr on VLDL metabolism and atherosclerosis

摘要 动脉粥样硬化对老年人口心脏相关发病率和死亡率有显著影响。 退伍军人。血浆低密度脂蛋白及其前体极低密度脂蛋白是两种 致动脉粥样硬化的脂蛋白。低密度脂蛋白通过滞留在血管内皮下间隙而引发动脉粥样硬化 动脉壁。他汀类药物介导的降低低密度脂蛋白目前是心血管疾病治疗的主要手段。 然而，尽管有效，但仍有许多反应迟钝和不容忍的情况。这样就有了 迫切需要其他降低血浆低密度脂蛋白的方法，最好是与 他汀类药物。长期以来，阻断肝脏极低密度脂蛋白的分泌和促进低密度脂蛋白的清除一直被认为是 有效的降低低密度脂蛋白策略。这些与他汀类药物的使用不同。很久以来，人们就知道 血浆磷脂酰乙醇胺(PE)水平是预测人类动脉粥样硬化的较好指标。然而，如何 对PE的调节以及PE与动脉粥样硬化之间的联系机制还不是很清楚。Pe是 极低密度脂蛋白是极低密度脂蛋白和低密度脂蛋白的重要脂类成分之一，其水平影响血管病变的发生发展。 动物模型中的动脉粥样硬化形成。因此，研究体育运动的调节机制可能会为降低 极低密度脂蛋白和低密度脂蛋白，并用于治疗人类动脉粥样硬化的新方法。 鞘磷脂合成酶基因家族有三个成员：SMS1和SMS2具有SM 合酶活性，而短信相关蛋白(SMSr)没有SM合酶活性，但有神经酰胺 试管中磷酸乙醇胺(CPE)合成酶活性。尽管SMSr普遍表达在 在所有被测试的组织中，大多数哺乳动物组织或细胞中的CPE水平在食物或 高脂肪/高胆固醇饮食。因此，SMSr在体内并不是一个功能性的CPE合成酶，而是它真正的生物学意义。 其功能有待阐明。从CPE合成酶反应中，我们注意到SMSR应该有一个 潜在的PE-PLC活性，即将PE水解为二酰甘油和磷乙醇胺，这可以 参与组织PE的稳态调节。根据这项研究的初步结果，我们随后 假设SMSr是体内有功能的PE-PLC。鉴于PE水平与极低密度脂蛋白有关 产生、清除低密度脂蛋白和动脉粥样硬化的发展，SMSr/PE-PLC应该是一种新的和 降低低密度脂蛋白的目标前景看好。我们有三个具体目标：1.调查短信是否是一种 功能PE-PLC。2.评价阻断SMSr/PE-PLC对极低密度脂蛋白产生和低密度脂蛋白的影响 通行证。3.探讨SMSr/PE-PLC缺陷在动脉粥样硬化发生发展中的作用。真知灼见 从拟议的研究中获得的信息将使我们能够评估SMSr/PE-PLC作为预防和 治疗人类动脉粥样硬化。

Summary Atherosclerosis contributes significantly to cardiac related morbidity and mortality in the aging population of veterans. Plasma low density lipoprotein (LDL) and its precursor very low density lipoprotein (VLDL) are two atherogenic lipoproteins. LDL initiates atherosclerosis through its retention in the subendothelial space of arterial walls. Statin-mediated LDL lowering is now the mainstay of cardiovascular disease treatment. However, despite the efficacy, there are many instances of unresponsiveness and intolerance. There is thus an urgent need for additional approaches for lowering plasma LDL, preferably acting synergistically with statins. Blocking liver VLDL secretion and promoting LDL clearance have long been recognized as an effective LDL lowering strategies. Those are different from the use of statins. It is known for a long time that plasma phosphatidylethanolamine (PE) level is a better predictor for human atherosclerosis. However, how to regulate PE and what is the mechanism linking PE with atherosclerosis are not quite understood. PE is one of the important lipid components on VLDL and LDL, and its level influences the development of atherogenesis in animal models. Thus, study PE regulation may provide an important clue for lowering VLDL and LDL, and for a new treatment of human atherosclerosis. Sphingomyelin synthase (SMS) gene family has three members: SMS1 and SMS2 have SM synthase activity, while SMS-related protein (SMSr) has no SM synthase activity but has ceramide phosphorylethanolamine (CPE) synthase activity in test tubes. Although SMSr is ubiquitously expressed in all tested tissues, the CPE levels in most of mammalian tissues or cells are undetectable under chow or high fat/cholesterol diets. Therefore, SMSr is not a functional CPE synthase in vivo and its real biological function need to be elucidated. From the CPE synthase reaction, we notice that SMSr should have a potential PE-PLC activity, i.e. hydrolyzing PE into diacylglycerol and phosphorylethanolamine, which could be involved in tissue PE steady state regulation. Based on preliminary results of this study, we then hypothesize that SMSr is a functional PE-PLC in vivo. Given the fact that PE levels are involved in VLDL production, LDL clearance, and the development of atherosclerosis, SMSr/PE-PLC should be a novel and promising target for lowering LDL. We have three specific aims: 1. Investigate whether SMSr is a functional PE-PLC. 2. Evaluate the effects of blocking SMSr/PE-PLC on VLDL production and LDL clearance. 3. Examine the role of SMSr/PE-PLC deficiency in the development of atherosclerosis. Insights gained from the proposed studies will allow us to evaluate SMSr/PE-PLC as a target for preventing and treating human atherosclerosis.