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

简介(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的心血管疾病的高危因素。为了提供治疗干预的机会，了解动脉粥样硬化的病理生理途径是很重要的。这项应用侧重于确定在动脉粥样硬化病变中驱动泡沫细胞形成的机制。酰基辅酶A：胆固醇酰基转移酶1(ACAT1)已成为治疗动脉粥样硬化的潜在靶点，这可能是因为它的催化活性，包括将游离胆固醇转化为胆固醇酯。胆固醇酯是巨噬细胞泡沫细胞中脂滴的主要成分。在动物模型中测试抑制ACAT1是否可以预防动脉粥样硬化的研究导致了关于其益处的相互矛盾的观点。这一争议源于对ACAT1的药理抑制导致斑块稳定性的改善，而通过全局Acat1基因敲除(Acat1-/-)抑制ACAT1不会导致斑块大小改变。斑块形态的改变被推测归因于巨噬细胞中缺乏ACAT1。然而，我们的实验室最近发现，全局Acat1基因敲除(KO)会影响ACAT1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。造血干细胞的改变会导致白细胞增多，这是动脉粥样硬化的一个危险因素。因此，全球Acat1 KO可能会产生许多未知的影响和后果。巨噬细胞ACAT1在动脉粥样硬化中的作用尚不清楚。Aim 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(Acat1-M-M)来解决这一问题，作为一种工具来研究髓系ACAT1缺失对动脉粥样硬化进展的影响。我们将表征和比较APOE-/-、APOE-/-/Acat1-/-和APOE-/-/Acat1-M-M小鼠在早期和晚期动脉粥样硬化病变中的斑块形成和形态。此前有研究表明，在高胆固醇代谢状态下(即在APOE缺乏或低密度脂蛋白受体缺乏的背景下)，全球Acat1 KO会导致黄瘤病变加速生长，当游离胆固醇在真皮皮下积聚时就会出现这种情况。这种不良反应被推测归因于巨噬细胞中缺乏ACAT1。在目标2中，我们建议通过使用APOE-/-/Acat1-M-M小鼠来检验这一解释的有效性，以研究巨噬细胞特异性缺失ACAT1对黄瘤病进展的影响。

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.