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

骨髓 ACAT1 耗竭对动脉粥样硬化和 Xanth 进展的影响

• 批准号: 8784798
• 负责人: Elaina Marie Melton
• 金额: $ 5.7万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-26 至 2016-09-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8784798
• 关键词: Address; Adverse effects; Animal Model; Antiatherogenic; ApoE knockout mouse; Apolipoprotein E; Arterial Fatty Streak; Atherogenic Diet; Atherosclerosis; Cardiovascular Diseases; Cell Lineage; Cells; Cholesterol; Cholesterol Esters; Conflict (Psychology); Cutaneous; Dermis; Development; Disease; Enzyme-Linked Immunosorbent Assay; Enzymes; Epidemic; Esterification; Exhibits; Foam Cells; Foundations; Goals; Growth; Health; Hematopoietic stem cells; Human; Inflammatory; Knock-out; Knockout Mice; Laboratories; Lesion; Leukocytosis; Lipids; Low Density Lipoprotein Receptor; Metabolic; Molecular Profiling; Morphology; Mus; Myelogenous; Pathologic Processes; Pathway interactions; Physiological; Plasma; Play; Public Health; Reporting; Research; Risk Factors; Role; Skin; Solid; Staging; Surface; Testing; Therapeutic Intervention; Tissues; Western Blotting; Work; Xanthomas; Xanthomatosis; atherogenesis; base; cell type; cytokine; design; driving force; feeding; high risk; improved; insight; macrophage; mouse model; novel; prevent; skin lesion; stem; sterol O-acyltransferase 1; subcutaneous; tool

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.

描述（由申请人提供）：心血管疾病是一个公共卫生问题，在美国持续的证据中仍然是一个具有挑战性的流行病，表明动脉粥样硬化是患血管性心血管疾病的高风险因素。为了提供治疗干预的机会，重要的是要了解动脉粥样硬化涉及的病态生理途径。该应用着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-COA：胆固醇酰基转移酶1（ACAT1）已浮出水面作为动脉粥样硬化治疗的潜在靶标，这可能是由于其催化活性涉及将游离胆固醇转化为胆固醇酯的催化活性。胆固醇酯是巨噬细胞泡沫细胞中脂质液滴的主要成分。进行测试抑制ACAT1是否可以防止动物模型中的动脉粥样硬化的研究导致对其益处的看法相互矛盾。这一争议源于对ACAT1的药理抑制的报道，导致牙菌斑的稳定性提高，而全球ACAT1敲除（ACAT1 - / - ）抑制ACAT1导致牙菌斑大小的变化没有变化。据推测，斑块形态的改变归因于巨噬细胞中缺乏ACAT1。但是，最近我们的实验室表明，全球ACAT1基因敲除（KO）会影响多种组织和细胞类型中ACAT1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待澄清。 AIM 1中提出的工作旨在通过使用最近在我们的实验室（ACAT1-M-M）中创建的新型小鼠系来解决此问题，以检查髓样ACAT1耗竭对动脉粥样硬化进展的影响。我们将表征和比较ApoE-/ - ，ApoE-/ - / - /ACAT1-/ - 与ApoE-/ - / - / - / - / - / - / - /ACAT1-M-M MICE喂养动脉粥样硬化饮食的早期和晚期动脉粥样硬化病变中的斑块形成和形态。以前表明，在高胆固醇血症代谢状态下的全球ACAT1 KO（即在APOE缺乏或低密度脂蛋白受体受体不足的背景下）会导致Xanthoma损伤的加速生长，当胆固醇在Dermis的皮下层中自由累积时，会产生。据推测，这种不良影响归因于巨噬细胞中缺乏ACAT1。在AIM 2中，我们建议通过使用APOE - / - /ACAT1-M-M小鼠来研究巨噬细胞特定的ACAT1缺失对Xanthomatomis病的进展的影响。