Inflammation, Atherosclerosis and ApoA-I

描述(由申请人提供)：加速的动脉粥样硬化表现为一种复杂的发病机制，包括血脂的改变，涉及免疫系统的炎症状态。高密度脂蛋白载脂蛋白A-I主要通过组织和招募免疫细胞中的胆固醇和氧化形式的胆固醇和磷脂来防止这些变化，保护免疫细胞免受失调和细胞凋亡的影响。在目前的方案中，我们将研究在低密度脂蛋白受体apoA-I双重敲除(DKO)小鼠中，导致免疫细胞胆固醇沉积、加速动脉粥样硬化和自身免疫表型发展的分子机制。在以前的研究中，当DKO和LDLR-/-(SKO)小鼠被喂食致动脉粥样硬化的食物时，DKO小鼠比SKO小鼠出现周围淋巴结(LNS)和脾的增大。DKO LN富含胆固醇酯(CE)，并含有大量富含CE的T、B细胞、树突状细胞和巨噬细胞。DKO患者血浆抗dsDNA抗体和氧化低密度脂蛋白抗体也升高，提示为自身免疫表型。当饮食喂养的DKO小鼠在开始饮食时用apoA-I治疗时，LN扩大和LN CE积聚都被“防止”。无论饮食中的胆固醇水平如何，DKO小鼠始终显示出比SKO小鼠更低的血浆胆固醇，但主动脉胆固醇沉积和炎症更多。因此，本研究的目的是利用DKO小鼠来研究apoA-I在饮食喂养的DKO小鼠动脉粥样硬化的进展和消退过程中，1)调节CE和氧固醇在淋巴细胞中的积聚和激活，2)改变CE负载的淋巴细胞的增殖和/或凋亡，3)影响T细胞和DC在斑块浸润中的作用。

DESCRIPTION (provided by applicant): 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-Idouble 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.