Role of ACAT1 in Pathological Retinal Neovascularization

ACAT1 在病理性视网膜新生血管形成中的作用

• 批准号: 10355501
• 负责人: Ruth B Caldwell
• 金额: $ 18.67万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355501
• 关键词: Abbreviations; Acyl Coenzyme A; Alzheimer' s Disease; Amplifiers; Area; Atherosclerosis; Blindness; Blood Vessels; Brain Hypoxia-Ischemia; CSF1 gene; Cell Proliferation; Cells; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Clinical Trials; Coculture Techniques; Data; Diabetic Retinopathy; Disease; Dyslipidemias; Early Intervention; Endothelial Cells; Enzymes; Exposure to; Eye diseases; Goals; Hemorrhage; Hypoxia; In Vitro; Inflammatory; Intestines; Knock-out; Knockout Mice; LDL Cholesterol Lipoproteins; Lead; Lipids; Liver; Low Density Lipoprotein Receptor; Macrophage Activation; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Mediator of activation protein; Microglia; Minor; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Operative Surgical Procedures; Oxides; Oxygen; Pathologic; Pathology; Patients; Phenotype; Play; Prevention; Protein Isoforms; Research; Retina; Retinal Detachment; Retinal Diseases; Retinal Neovascularization; Retinopathy of Prematurity; Role; Signal Transduction; Sterol O-Acyltransferase; Sterols; TNF gene; Testing; Tissues; Transferase; Tube; Up-Regulation; Vascular Endothelial Growth Factors; Vegf Inhibitor; Vitrectomy; angiogenesis; base; cell growth; design; improved; in vivo; inhibitor; intravitreal injection; laser photocoagulation; lipid disorder; macrophage; migration; mouse model; new therapeutic target; normoxia; ocular angiogenesis; oxidized low density lipoprotein; prevent; promoter; receptor; receptor expression; repaired; retinal angiogenesis; sterol O-acyltransferase 1; sterol O-acyltransferase 2; treatment effect; vascular injury

PROJECT SUMMARY Studies in the mouse model of oxygen-induced retinopathy (OIR) have shown that macrophage- induced angiogenesis has a critical role in pathological retinal neovascularization (RNV) but the mechanisms are not yet known. We propose to investigate expression/activity of the cholesterol metabolizing enzyme ACAT (acyl-Coenzyme A: cholesterol acyltransferase, also known as sterol O-acyltranserase) as a novel therapeutic target for RNV. There are two isoforms of ACAT: ACAT1 and ACAT2. ACAT1 is widely expressed and its upregulation in macrophages or macrophage/microglia has been implicated in atherosclerosis and Alzheimer's disease, respectively. ACAT2 is mainly expressed in the intestines and liver. We will focus on ACAT1 in this project. During ischemia/hypoxia, macrophages are exposed to increased levels of oxidized low density lipoprotein cholesterol (oxLDLc). Its internalization by the LDL receptor (LDLR) increases activity of ACAT1, which esterifies cholesterol to form cholesterol esters (CE). Increases in CE promote an inflammatory macrophage phenotype characterized by increased expression of the amplifier of inflammatory signaling TREM-1 (triggering receptor expressed in myeloid cells-1), MCSF (macrophage colony stimulating factor), VEGF and TNFα. Our preliminary studies in the mouse OIR model show marked increases in lipid accumulation, LDLR expression and CE formation in areas of RNV suggesting that dyslipidemia and ACAT activity play a key role in RNV. Furthermore, LDLR deletion or ACAT inhibition prevented RNV and decreased expression of TREM-1, MCSF and VEGF. Moreover, hypoxia treatment of macrophages in vitro significantly increased their expression of TREM-1, MCSF and VEGF. Based on these results our central hypothesis is that LDLc-induced increases in ACAT1 and CE formation drive macrophage activation and pathological RNV in the mouse model of OIR (Fig. 1). Our aims will test this hypothesis by determining whether 1) Inhibition of ACAT1 prevents RNV in vivo, 2) Deletion of ACAT1 in myeloid derived cells prevents RNV in vivo and MΦ -induced angiogenesis in vitro.

项目概要 对氧诱导视网膜病变 (OIR) 小鼠模型的研究表明，巨噬细胞 诱导血管生成在病理性视网膜新生血管（RNV）中具有关键作用，但 我们建议研究胆固醇的表达/活性。 代谢酶ACAT（酰基辅酶A：胆固醇酰基转移酶，又称甾醇 O-酰基转移酶）作为 RNV 的新型治疗靶点 ACAT 有两种亚型：ACAT1。 ACAT2 广泛表达，并且在巨噬细胞中表达上调。 巨噬细胞/小胶质细胞与动脉粥样硬化和阿尔茨海默病有关， ACAT2 主要在肠道和肝脏中表达。 在缺血/缺氧期间，巨噬细胞暴露于氧化水平升高的环境中。 低密度脂蛋白胆固醇 (oxLDLc) 被 LDL 受体 (LDLR) 内化。 增加 ACAT1 的活性，ACAT1 可将胆固醇酯化形成胆固醇酯 (CE)。 CE 的增加会促进炎症巨噬细胞表型的增加，其特征是 炎症信号放大器 TREM-1 的表达（触发受体在 骨髓细胞-1)、MCSF（巨噬细胞集落刺激因子）、VEGF 和 TNFα。 小鼠 OIR 模型研究显示脂质积累、LDLR 表达显着增加 RNV 区域中的 CE 形成表明血脂异常和 ACAT 活性发挥着关键作用 此外，LDLR 缺失或 ACAT 抑制可阻止 RNV 并减少。 TREM-1、MCSF和VEGF的表达此外，巨噬细胞体外缺氧处理。 根据我们的这些结果，TREM-1、MCSF 和 VEGF 的表达显着增加。 中心假设是 LDLc 诱导 ACAT1 和 CE 形成驱动力增加 OIR 小鼠模型中的巨噬细胞激活和病理性 RNV（图 1）。 将通过确定 1) 抑制 ACAT1 是否可以预防体内 RNV，2) 来检验这一假设 骨髓来源细胞中 ACAT1 的缺失可防止体内 RNV 和 MΦ 诱导的血管生成 体外。