Effect of SMSr on VLDL metabolism and atherosclerosis

总结 动脉粥样硬化在老年人群中对心脏相关的发病率和死亡率有显著影响， 老兵血浆低密度脂蛋白（LDL）及其前体极低密度脂蛋白（VLDL）是两种 致动脉粥样硬化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LDL降低现在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。因此存在 迫切需要用于降低血浆LDL的另外的方法，优选地与 他汀类长期以来，阻断肝脏VLDL分泌和促进LDL清除被认为是一种有效的治疗方法。 有效的LDL降低策略。这与使用他汀类药物不同。长期以来，人们都知道， 血浆磷脂酰乙醇胺（PE）水平是一个更好的预测人类动脉粥样硬化。但如何 对PE的调控以及PE与动脉粥样硬化的联系机制尚不清楚。PE是 VLDL和LDL的重要脂质成分之一，其水平影响着 动物模型中的动脉粥样硬化。因此，研究体育调节可能为降低 VLDL和LDL，并用于治疗人类动脉粥样硬化的新方法。 鞘磷脂合成酶（SMS）基因家族有三个成员：SMS 1和SMS 2具有SM SM合成酶活性，而SMS相关蛋白（SMSr）没有SM合成酶活性，但具有神经酰胺 磷酸乙醇胺（CPE）合酶活性。尽管SMSr在细胞中普遍表达， 在所有测试的组织中，在大多数哺乳动物组织或细胞中的CPE水平在食物下是不可检测的，或 高脂肪/高胆固醇饮食。因此，SMSr在体内不是功能性CPE合成酶，其真实的生物学活性可能与其代谢产物的活性有关。 功能需要明确。从CPE合成酶反应中，我们注意到SMSr应该具有一个 潜在的PE-PLC活性，即将PE水解成二酰基甘油和磷酸乙醇胺，其可以 参与组织PE稳态调节。根据这项研究的初步结果，我们 假设SMSr是体内功能性PE-PLC。考虑到PE水平与VLDL有关， 因此，SMSr/PE-PLC可能是一种新的， 降低LDL的有希望的目标。我们有三个具体目标：1。调查SMSr是否为 功能PE-PLC。2.评价阻断SMSr/PE-PLC对VLDL产生和LDL 间隙3.研究SMSr/PE-PLC缺乏在动脉粥样硬化发展中的作用。见解 从拟议的研究中获得的将使我们能够评估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.