Novel Mechanisms Underlying the Development of Atherosclerosis

动脉粥样硬化发展的新机制

• 批准号: 10589484
• 负责人: Shiyou Chen
• 金额: --
• 依托单位: HARRY S. TRUMAN MEMORIAL VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589484
• 关键词: Acute myocardial infarction; Acyl Coenzyme A; Antibodies; Aorta; Apolipoprotein E; Apoptosis; Arterial Fatty Streak; Arterial Intimas; Arteries; Aspirin; Atherosclerosis; Biochemical; Blood flow; CCAAT-Enhancer-Binding Proteins; Cardiovascular system; Cell Lineage; Cell physiology; Cells; Cholesterol; Cholesterol Esters; Chronic; Clinical; Complex; Coronary Arteriosclerosis; Coronary artery; Data; Development; Disease; Down-Regulation; Elements; Event; Fibrates; Foam Cells; General Population; Goals; Heart failure; High Density Lipoprotein Cholesterol; High Fat Diet; Histologic; Homologous Protein; Hospitalization; Human; In Vitro; Inflammatory; Inflammatory Response; Interleukin-1 beta; Lesion; Lipids; Macrophage; Mediating; Molecular; Molecular Target; Morbidity - disease rate; Mus; Myelogenous; Nuclear; Outcome; Pathway interactions; Pharmaceutical Preparations; Phenotype; Play; Prevention; Progressive Disease; Proteins; Role; Serum; Signal Pathway; Signal Transduction; Signaling Protein; Smooth Muscle Myocytes; Sterol O-Acyltransferase; Stroke; Testing; Therapeutic; Therapeutic Agents; Vascular Smooth Muscle; Veterans; atherogenesis; cardiovascular health; effective therapy; genetic approach; high risk; improved; in vivo; inhibitor; knock-down; loss of function; military veteran; mortality; new therapeutic target; novel; olfactomedin; overexpression; oxidized low density lipoprotein; pharmacologic; protein expression; sterol O-acyltransferase 1; therapeutic development; vascular inflammation

Project Summary Coronary atherosclerosis is one of five top causes for cardiovascular (CV) hospitalization in U.S. Veterans. Atherosclerosis is a complex and progressive disease characterized by the buildup of plaques composed of lipid- rich foam cells, inflammatory cells, and fibrous elements in the arterial intima. Atherosclerosis is associated with high risks of acute myocardial infarction, heart failure, and stroke, which are the additional three of top five causes for Veterans cardiovascular hospitalization. It is well established that vascular smooth muscle cell (SMC) and nuclear factor (NF)-kB signaling contribute to development and progression of atherosclerosis. However, the factors and mechanisms that govern SMC function in atherosclerosis, remain largely unknown. Our exciting preliminary data indicate that Olfactomedin 2 (Olfm2) plays an essential role in the development of atherosclerosis. Olfm2 is induced in lipid-loading SMCs during SMC foam cell formation and in mouse and human atherosclerotic lesions. Importantly, Olfm2 deficiency (Olfm2-/-) inhibits high fat diet-induced atherosclerotic plaque formation and improves plaque stability in advanced atherosclerosis. Biochemically, Olfm2-/- elevates serum level of high-density lipoprotein-cholesterol while downregulates the expression of acyl- coenzyme A: cholesterol acyltransferase-1 (ACAT1) in aortas of ApoE-/- mice. ACAT1 converts free cholesterol into cholesteryl esters for storage in lipid droplets and thus promotes foam cell formation in atherosclerotic lesion. In vitro studies showed that knockdown of Olfm2 inhibits while overexpression of Olfm2 promotes lipid accumulation and CCAAT/enhancer-binding protein homologous protein (CHOP) expression in oxidized low- density lipoprotein-treated SMCs. These data strongly support a novel hypothesis that Olfm2 promotes atherosclerosis by mediating SMC foam cell formation and apoptosis. Using primary human coronary artery SMCs, Olfm2-/- mouse SMCs, and SMC lineage-tracing Olfm2-/- mice combining with molecular, cellular, histological, and pharmacological approaches, we will 1) test if Olfm2 promotes SMC foam cell formation and mediates SMC foam cell apoptosis; 2) determine the molecular mechanisms underlying Olfm2 function in mediating SMC foam cell formation and apoptosis; and 3) determine the cell-specific roles of Olfm2 in atherosclerosis in vivo. Successful Completion of the proposed studies will unravel a novel mechanism underlying Olfm2 function in atherogenesis, which may ultimately lead to the development of therapeutic strategies against atherosclerosis in Veterans and general populations.

项目概要 冠状动脉粥样硬化是美国退伍军人心血管 (CV) 住院的五个主要原因之一。 动脉粥样硬化是一种复杂的进行性疾病，其特征是由脂质组成的斑块积聚。 动脉内膜中有丰富的泡沫细胞、炎症细胞和纤维成分。动脉粥样硬化与以下因素有关 急性心肌梗塞、心力衰竭和中风的高风险，是前五位原因中的另外三个 退伍军人心血管住院。众所周知，血管平滑肌细胞（SMC）和 核因子 (NF)-kB 信号传导有助于动脉粥样硬化的发生和进展。然而， 控制动脉粥样硬化中 SMC 功能的因素和机制仍然很大程度上未知。我们激动人心的 初步数据表明 Olfactomedin 2 (Olfm2) 在 动脉粥样硬化。 Olfm2 在 SMC 泡沫细胞形成过程中以及在小鼠和小鼠体内的脂质负载 SMC 中被诱导。 人类动脉粥样硬化病变。重要的是，Olfm2 缺乏 (Olfm2-/-) 抑制高脂肪饮食诱导的 动脉粥样硬化斑块形成并改善晚期动脉粥样硬化斑块稳定性。从生化角度来说， Olfm2-/- 升高高密度脂蛋白胆固醇的血清水平，同时下调酰基- 辅酶 A：ApoE-/- 小鼠主动脉中的胆固醇酰基转移酶-1 (ACAT1)。 ACAT1 转化游离胆固醇 转化为胆固醇酯并储存在脂滴中，从而促进动脉粥样硬化病变中泡沫细胞的形成。 体外研究表明，Olfm2 的敲低会抑制脂质，而 Olfm2 的过表达则会促进脂质 氧化低-中的积累和CCAAT/增强子结合蛋白同源蛋白（CHOP）的表达 密度脂蛋白处理的 SMC。这些数据有力地支持了 Olfm2 提出的一个新假设 通过介导 SMC 泡沫细胞的形成和凋亡来预防动脉粥样硬化。使用人类原发冠状动脉 SMC、Olfm2-/- 小鼠 SMC 和 SMC 谱系追踪 Olfm2-/- 小鼠结合分子、细胞、 通过组织学和药理学方法，我们将 1) 测试 Olfm2 是否促进 SMC 泡沫细胞形成和 介导SMC泡沫细胞凋亡； 2)确定Olfm2功能的分子机制 介导 SMC 泡沫细胞形成和凋亡； 3) 确定 Olfm2 在细胞中的特定作用 体内动脉粥样硬化。成功完成拟议的研究将揭示一种新的机制 Olfm2 在动脉粥样硬化形成中的潜在功能，可能最终导致治疗药物的开发 退伍军人和普通人群的动脉粥样硬化策略。