Role of apolipoprotein E4 in the progression and regression of atherosclerosis

描述（由申请人提供）：动脉粥样硬化及其并发症仍然是美国死亡和残疾的主要原因。虽然促进动脉粥样硬化的消退已成为一种有希望的动脉粥样硬化治疗策略，但协调这一临床相关过程的分子和细胞机制尚不清楚。此外，载脂蛋白4 （apoE4）等位基因易导致有症状的动脉粥样硬化的机制，以及它是否会损害血脂降低后动脉粥样硬化的消退，在很大程度上仍是未知的。为了填补这些知识空白，我们提出了一系列apoE4、条件apoE表达、可逆性高脂血症和动脉粥样硬化退化的基因工程小鼠模型实验。亚形态ApoeR61h/h小鼠表达apoE4样形式的小鼠apoE （Arg-61 apoE）水平降低，再现了人类apoE4独特的生物物理特征，称为“结构域相互作用”。我们之前的研究表明，Arg- 61 apoE的结构域相互作用足以在高脂血症小鼠血浆中重现人类apoE4的vldl结合偏好。此外，我们在ApoeR61h/h小鼠中对apoE条件表达的研究最近证实，apoE除了降低血浆胆固醇水平外，还可以促进动脉粥样硬化的消退。

DESCRIPTION (provided by applicant): Atherosclerosis and its complications remain leading causes of death and disability in the United States. Although promoting the regression of atherosclerosis has emerged as a promising treatment strategy for atherosclerosis, the molecular and cellular mechanisms that orchestrate this clinically relevant process are poorly understood. Moreover, the mechanisms by which the apolipoprotein 4 (apoE4) allele predisposes to symptomatic forms of atherosclerosis and whether it can impair its regression following plasma lipid lowering, remains largely unknown. To fill these gaps of knowledge, we propose a series of experiments with genetically engineered murine models of apoE4, conditional apoE expression, reversible hyperlipidemia, and atherosclerosis regression developed in our laboratory. Hypomorphic ApoeR61h/h mice express reduced levels of an apoE4-like form of murine apoE (Arg-61 apoE) that reproduces a unique biophysical feature of human apoE4 called "domain interaction". Our previous studies have shown that domain interaction in Arg- 61 apoE is sufficient to reproduce the VLDL-binding preference of human apoE4 in hyperlipidemic mouse plasma. Moreover, our studies of conditional expression of apoE in ApoeR61h/h mice has recently established the existence of a role for apoE in promoting the regression of atherosclerosis beyond lowering plasma cholesterol levels. Experiments detailed in this proposal will make use of ApoeR61h/h mice, as well as new variants of this model, to investigate mechanisms by which apoE accumulation in plasma and macrophage-derived apoE in lesions regulate the onset and progression of atherosclerosis in the setting of hyperlipidemia. We will also test the hypothesis that apoE4 domain interaction in Arg-61 apoE will accelerate the progression of atherosclerosis and impair its regression following sustained lipid lowering. Lastly, we will test the hypothesis that apoE expression levels influence the migration of monocytes into established lesions, and the egress of macrophages from lesions during the regression of atherosclerosis in an isoform-specific manner. Our long term goal is to clarify the molecular and cellular mechanisms by which apoE isoforms regulate the progression and regression of atherosclerosis. A better understanding of these mechanisms would help usher in a new generation of molecular therapies to fight atherosclerosis, particularly among apoE4 carriers who represent 20% of the global population.