Inflammation, Atherosclerosis and ApoA-I

加速的动脉粥样硬化显示出复杂的发病机制，包括动脉粥样硬化的改变。 脂质，炎症状态涉及免疫系统。HDL apoA-I可以保护这些 改变主要是通过其组织和招募胆固醇和含氧化合物的能力， 免疫细胞中的胆固醇和磷脂形式保护它们免受 失调和凋亡。在目前的建议中，我们将研究分子 负责免疫细胞胆固醇沉积，加速 动脉粥样硬化和自身免疫表型的发展， LDL受体apoA-I双敲除（DKO）小鼠中的致动脉粥样硬化饮食。在以前的研究中， 当给DKO和LDLr-/-（SKO）小鼠喂食致动脉粥样硬化饮食时，DKO小鼠发生 与SKO小鼠相比，外周淋巴结（LN）和脾脏增大。DKO LN 富含胆固醇酯（CE），并含有扩大的CE群体 富集的T、B、树突细胞和巨噬细胞。抗dsDNA和氧化的血浆抗体 DKO中LDL也增加，提示自身免疫表型。两个LN 当饮食喂养的DKO小鼠， 在开始饮食时用apoA-I治疗。无论饮食水平如何， 胆固醇，DKO小鼠的血浆胆固醇始终低于SKO小鼠，但 更大的主动脉胆固醇沉积和炎症因此，本提案的目的 是用DKO小鼠研究apoA-I 1）调节CE的机制 和氧固醇积累和活化，2）改变增殖和/或 CE负载的淋巴细胞的凋亡，3）影响T细胞和DC对 饮食喂养的DKO中动脉粥样硬化进展和消退中的斑块浸润 小鼠

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.