Effect of sphingomyelin biosynthesis on atherosclerosis

摘要 大量证据表明，主动脉壁和血浆中鞘磷脂(SM)的含量密切相关。 与动脉粥样硬化形成有关。高SM是人类冠心病的独立危险因素， 与人类动脉粥样硬化斑块炎症有关。我们发现抑制丝氨酸棕榈酰- 转移酶是SM生物合成的第一种酶，可减少小鼠模型中血浆SM和动脉粥样硬化的发生。 然而，机制尚不清楚，这促使进一步的研究探索阻止SM之间的关系 合酶(Sms)与动脉粥样硬化的发生。SMS的两种亚型(SMS1和SMS2)位于丝氨酸的下游 棕榈酰转移酶，并催化神经酰胺转化为SM。SMS1和SMS2活动是共同的 在所有受试组织中都有表达，包括肝脏、肠道和巨噬细胞。因此，无论是SMS1基因，还是 基因敲除(KO)或SMS2KO方法都不足以评估SM降低对动脉粥样硬化的影响。 在本研究中，我们将使用SMS1/SMS2双KO方法。我们的目标是检验我们的假设 抑制总的SMS活性可以：A)在含载脂蛋白B的过程中阻断SM的生物利用度 致动脉粥样硬化性脂蛋白(BLP，即极低密度脂蛋白和乳胶粒)的产生；b)减少脂类的吸收和减弱 通过减少细胞(肠细胞和巨噬细胞)质膜脂筏中的SM而引起炎症；以及c)减少 动脉粥样硬化的进展和消退而不引起脂肪变性(短信抑制介导的神经酰胺 堆积会抑制脂肪生成)。在这项研究中，我们将使用可诱导的全局、肝脏特异性和 肠道特定的总短信KO小鼠模型，以及我们特定的短信抑制剂。具体目标：1. 评价阻断丹参对极低密度脂蛋白生成和分解代谢的影响。2.调查封堵效果 对脂肪吸收和乳糜粒分泌的影响。3.考察短信缺失或抑制在脑内的作用 动脉粥样硬化的进展和消退。从拟议的研究中获得的见解将使我们能够评估 作为防治动脉粥样硬化的靶点。

Summary Significant evidence indicates that sphingomyelin (SM) content in the aortic wall and in the plasma is closely related to atherogenesis. High SM is an independent risk factor for human coronary heart disease and is associated with human atherosclerotic plaque inflammation. We found that inhibiting serine palmitoyl- transferase, the first enzyme for SM biosynthesis reduced plasma SM and atherogenesis in mouse models. However, mechanisms are unknown, prompting further studies exploring relationships between blocking SM synthase (SMS) and atherogenesis. Two isoforms of SMS (SMS1 and SMS2) reside downstream of serine palmitoyl-transferase and catalyze the conversion of ceramide to SM. SMS1 and SMS2 activities are co- expressed in all tested tissues, including the liver, intestine, and macrophage. Thus, neither SMS1 gene knockout (KO) nor SMS2 KO approach is sufficient to evaluate the effect of SM reduction on atherosclerosis. We will use SMS1/SMS2 double KO approach in this study. Our objective is to test our hypotheses that inhibition of total SMS activity can: a) block SM bioavailability during the process of apoB-containing atherogenic lipoprotein (BLp, i.e. VLDL and chylomicron) production; b) reduce lipid absorption and attenuate inflammation by reducing SM in cell (enterocyte and macrophage) plasma membrane lipid rafts; and c) reduce atherosclerosis progression and regression without causing steatosis (SMS inhibition-mediated ceramide accumulation could suppress lipogenesis). In this study, we will use inducible global, liver-specific, and intestine-specific total SMS KO mouse models, as well as our specific SMS inhibitors. Specific aims: 1. Evaluate effects of blocking SMS on VLDL production and catabolism. 2. Investigate the effects of blocking SMS on lipid absorption and chylomicron secretion. 3. Examine the roles of absence or inhibition of SMS in atherosclerosis progression and regression. Insights gained from the proposed studies will allow us to evaluate SMS as a target for preventing and treating atherosclerosis.