Impact of Myeloid ACAT1 Depletion on the Progression of Atherosclerosis and Xanth

描述（由申请人提供）：心血管疾病是一个公共卫生问题，在美国仍然是一个具有挑战性的流行病。越来越多的证据表明，动脉粥样硬化是血脂异常性心血管疾病的高危因素。为了提供治疗干预的机会，重要的是要了解动脉粥样硬化的病理生理途径。本申请的重点是确定驱动动脉粥样硬化病变中泡沫细胞形成的机制。酰基辅酶A：胆固醇酰基转移酶1（ACAT 1）已成为动脉粥样硬化治疗的潜在靶点，可能是由于其催化活性，涉及游离胆固醇转化为胆固醇酯。胆固醇酯是巨噬泡沫细胞中脂滴的主要成分。在动物模型中测试抑制ACAT 1是否可以预防动脉粥样硬化的研究导致了对其益处的相互矛盾的观点。这一争议源于ACAT 1的药理学抑制导致斑块稳定性改善的报道，而通过整体Acat 1敲除（Acat 1-/-）抑制ACAT 1导致斑块大小无变化。推测斑块形态的改变归因于巨噬细胞中ACAT 1的缺乏。然而，最近我们的实验室已经表明，全球Acat 1敲除（KO）影响ACAT 1在多种组织和细胞类型中的表达，包括造血干细胞谱系中的细胞。造血干细胞的改变可导致白细胞增多，这是动脉粥样硬化的危险因素。因此，全球Acat 1 KO可能会产生许多未知的影响和后果。巨噬细胞ACAT 1在动脉粥样硬化中的作用仍有待阐明。目标1中提出的工作旨在通过使用我们实验室最近创建的一种新的小鼠系（Acat 1-M-M）来解决这个问题，作为检查骨髓ACAT 1缺失对动脉粥样硬化进展的影响的工具。我们将描述和比较Apoe-/-、Apoe-/-/Acat 1-/-和Apoe-/-/Acat 1-M-M小鼠（喂食致动脉粥样硬化饲料）早期和晚期动脉粥样硬化病变中的斑块形成和形态。先前显示，在高胆固醇血症代谢状态下（即在Apoe缺陷或低密度脂蛋白受体缺陷背景下），整体Acat 1 KO导致黄瘤病变的加速生长，当游离胆固醇在真皮的皮下层中积聚时，黄瘤病变出现。据推测，这种不良反应归因于巨噬细胞中缺乏ACAT 1。在目标2中，我们建议通过使用Apoe-/- /Acat 1-M-M小鼠来研究巨噬细胞特异性缺失ACAT 1对黄瘤病进展的影响，以测试这种解释的有效性。

DESCRIPTION (provided by applicant): Cardiovascular disease is a public health issue and continues to be a challenging epidemic in the U.S. Mounting evidence suggests that atherosclerosis is a high risk factor for dyslipidemic cardiovascular disease. To offer opportunities for therapeutic intervention, it is important to understand the patho-physiological pathways involved in atherosclerosis. This application focuses on determining the mechanisms which drive foam cell formation in atherosclerotic lesions. Acyl-CoA:cholesterol acyltransferase 1 (ACAT1) has surfaced as a potential target for atherosclerosis treatment, likely due its catalytic activity which involves conversion of free cholesterol into cholesterol esters. Cholesterol esters are major components of lipid droplets in macrophage foam cells. Research conducted to test whether inhibiting ACAT1 can prevent atherosclerosis in animal models resulted in conflicting opinions regarding its benefits. This controversy stems from reports of pharmacological inhibition of ACAT1 resulting in improvement of plaque stability, while inhibiting ACAT1 by global Acat1 knockout (Acat1-/-) resulted in no change in plaque size. Alterations in plaque morphology were speculated to be attributed to the lack of ACAT1 in macrophages. However, recently our laboratory has shown that global Acat1 knockout (KO) impacts expression of ACAT1 in multiple tissues and cell types, including cells in the hematopoietic stem cell lineage. Alterations in hematopoietic stem cells can result in leukocytosis, which is a risk factor for atherosclerosis. Therefore, global Acat1 KO may produce many unknown effects and consequences. The role of macrophage ACAT1 in atherosclerosis remains to be clarified. The work proposed in Aim 1 is designed to address this issue by using a novel mouse line recently created in our laboratory, (Acat1-M-M), as a tool to examine the impact of myeloid ACAT1 depletion on atherosclerosis progression. We will characterize and compare plaque formation and morphology in early and late stage atherosclerotic lesions between the Apoe-/-, Apoe-/-/Acat1-/- and the Apoe-/-/Acat1-M-M mice fed an atherogenic diet. Previously it was shown that global Acat1 KO under a hypercholesterolemic metabolic state (i.e. under an Apoe deficient or low density lipoprotein receptor deficient background) results in accelerated growth of xanthoma lesions, which arise when free cholesterol builds up in the subcutaneous layer of the dermis. This adverse effect was speculated to be attributed to the lack of ACAT1 in macrophages. In aim 2, we propose to test the validity of this interpretation by using the Apoe-/- /Acat1-M-M mice to study the effects of macrophages specific deletion of ACAT1 on the progression of xanthomatosis.