Effect of sphingomyelin biosynthesis on atherosclerosis

总结 有重要证据表明，主动脉壁和血浆中的鞘磷脂（SM）含量密切相关， 与动脉粥样硬化有关。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相关。我们发现抑制丝氨酸棕榈酰- 在小鼠模型中，SM生物合成的第一种酶- 然而，机制尚不清楚，促使进一步研究探索阻断SM之间的关系， 合成酶（SMS）与动脉粥样硬化形成的关系。SMS的两种亚型（SMS 1和SMS 2）位于丝氨酸的下游， 棕榈酰转移酶和催化神经酰胺转化为SM。SMS 1和SMS 2活动是共同的， 在所有测试的组织中表达，包括肝脏、肠和巨噬细胞。因此，SMS 1基因 基因敲除（KO）或SMS 2 KO方法足以评估SM减少对动脉粥样硬化的影响。 我们将在本研究中使用SMS 1/SMS 2双KO方法。我们的目标是验证我们的假设， 总SMS活性的抑制可以：a）在含apoB的过程中阻断SM的生物利用度， 致动脉粥样硬化脂蛋白（BLp，即VLDL和乳糜微粒）的产生; B）减少脂质吸收并减弱 通过减少细胞（肠细胞和巨噬细胞）质膜脂筏中的SM来减轻炎症;和 不引起脂肪变性的动脉粥样硬化进展和消退（SMS抑制介导的神经酰胺 积累可抑制脂肪生成）。在这项研究中，我们将使用诱导型全球，肝脏特异性， 精氨酸特异性总SMS KO小鼠模型，以及我们的特异性SMS抑制剂。具体目标：1. 评价阻断SMS对VLDL产生和催化的影响。2.调查阻塞的影响 SMS对脂质吸收和乳糜微粒分泌的影响。3.检查SMS的缺失或抑制在 动脉粥样硬化进展和消退。从拟议的研究中获得的见解将使我们能够评估 SMS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.