Inflammation, Atherosclerosis and ApoA-I

加速的动脉粥样硬化表现出复杂的发病机制，包括 脂质，涉及免疫系统的炎症状态。高密度脂蛋白载脂蛋白A-I可预防这些 变化主要通过其组织和吸收胆固醇和含氧量的能力来实现 来自免疫细胞的胆固醇和磷脂形式，保护它们免受 调节失调和细胞凋亡。在目前的提案中，我们将研究分子 免疫细胞胆固醇沉积机制加速 动脉粥样硬化与自身免疫表型的发展 低密度脂蛋白受体，载脂蛋白A-I双基因敲除(DKO)小鼠的致动脉粥样硬化饮食。在之前的研究中， 当给DKO和LDLR-/-(SKO)小鼠喂食致动脉粥样硬化的食物时，DKO小鼠发育成 与SKO小鼠相比，周围淋巴结(LNS)和脾肿大。DKO LN 富含胆固醇酯(CE)，并含有更多的CE 浓缩T、B、树突状细胞和巨噬细胞。血浆中抗dsDNA抗体和氧化 DKO患者的低密度脂蛋白也升高，提示为自身免疫表型。两个LN 当喂食DKO小鼠时，肥大和LN CE积聚被“阻止” 在开始饮食时用载脂蛋白A-I治疗。无论饮食水平如何 胆固醇，DKO小鼠的血浆胆固醇一直低于SKO小鼠，但 更大的主动脉胆固醇沉积和炎症。因此，这项提议的目标是 目的是利用DKO小鼠研究载脂蛋白A-I调节CE的机制 和氧固醇在淋巴细胞中的积聚和激活，2)改变淋巴细胞的增殖和/或 CE负载淋巴细胞的凋亡，3)影响T细胞和DC对 饮食DKO大鼠动脉粥样硬化进展和消退过程中的斑块渗透 老鼠。

Accelerated atherosclerosis displays a complex pathogenesis including alterations in lipids, inflammatory state involving the immune system. HDL apoA-I protects against these changes mainly through its ability to organize and recruit cholesterol and oxygenated forms of cholesterol and phospholipids from immune cells protecting them from dysregulation and apoptosis. In the current proposal, we will investigate the molecular mechanisms responsible for immune cell cholesterol deposition, accelerated atherosclerosis and the development of an autoimmune phenotype in response to an atherogenic diet in LDL receptor, apoA-I double knockout (DKO) mice. In previous studies, when DKO and LDLr-/- (SKO) mice were fed an atherogenic diet, DKO mice developed enlarged peripheral lymph nodes (LNs) and spleens compared to SKO mice. DKO LN were enriched in cholesterol ester (CE) and contained expanded populations of CE enriched T, B, dendritic cells and macrophages. Plasma antibodies to dsDNA and oxidized LDL were also increased in DKO suggesting an autoimmune phenotype. Both LN enlargement and LN CE accumulation were "prevented" when diet-fed DKO mice were treated with apoA-I at the time the diet was initiated. Regardless of the level of dietary cholesterol, DKO mice consistently showed lower plasma cholesterol than SKO mice, yet greater aortic cholesterol deposition and inflammation. Therefore, the goal of this proposal is to use the DKO mouse to investigate the mechanisms by which apoA-I 1) modulates CE and oxysterol accumulation and activation in lymphocytes, 2) alters the proliferation and/or apoptosis of CE loaded lymphocytes, 3) affects the contribution of T cells and DC to plaque infiltration in both progression and regression of atherosclerosis in diet-fed DKO mice.