Inflammation, Atherosclerosis and ApoA-I

描述（由申请人提供）：加速性动脉粥样硬化表现出复杂的发病机制，包括脂质改变、涉及免疫系统的炎症状态。HDL apoA-I主要通过其组织和募集来自免疫细胞的胆固醇和胆固醇和磷脂的氧化形式的能力来保护它们免受失调和凋亡。在目前的建议中，我们将调查的分子机制，负责免疫细胞胆固醇沉积，加速动脉粥样硬化和发展的自身免疫表型，以响应致动脉粥样硬化饮食的LDL受体，apoA-I双敲除（DKO）小鼠。在先前的研究中，当DKO和LDLr-/-（SKO）小鼠喂食致动脉粥样硬化饮食时，与SKO小鼠相比，DKO小鼠发展出增大的外周淋巴结（LN）和脾脏。DKO LN富含胆固醇酯（CE）并含有CE富集的T、B、树突细胞和巨噬细胞的扩增群体。在DKO中，抗dsDNA和氧化LDL的血浆抗体也增加，表明自身免疫表型。当饮食喂养的DKO小鼠在饮食开始时用apoA-I处理时，LN增大和LN CE积累都被“阻止”。无论饮食胆固醇水平如何，DKO小鼠的血浆胆固醇始终低于SKO小鼠，但主动脉胆固醇沉积和炎症更大。因此，本发明的目的是使用DKO小鼠研究apoA-I 1）调节CE和氧固醇在淋巴细胞中的积累和活化，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对饮食喂养的DKO小鼠中动脉粥样硬化的进展和消退中的斑块浸润的贡献的机制。

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.