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.

项目摘要 冠状动脉粥样硬化是美国退伍军人心血管（CV）住院的五大原因之一。 动脉粥样硬化是一种复杂的进行性疾病，其特征在于由脂质组成的斑块的积聚， 动脉内膜中有丰富的泡沫细胞、炎性细胞和纤维成分。动脉粥样硬化与 急性心肌梗死、心力衰竭和中风的高风险，这是五大原因中的另外三个 退伍军人心血管住院治疗血管平滑肌细胞（SMC）和血管平滑肌细胞（SMC）是血管平滑肌细胞的重要组成部分。 核因子（NF）-kB信号通路参与动脉粥样硬化的发生和发展。但 在动脉粥样硬化中控制SMC功能的因素和机制在很大程度上仍然未知。整理的丰厚 初步数据表明，Olfactomedin 2（Olfm 2）在发展中起着至关重要的作用， 动脉粥样硬化在SMC泡沫细胞形成过程中，在载脂SMC中以及在小鼠和 人类动脉粥样硬化病变。重要的是，Olfm 2缺乏（Olfm 2-/-）抑制高脂饮食诱导的 动脉粥样硬化斑块形成和改善晚期动脉粥样硬化斑块稳定性。在生物化学上， Olfm 2-/-升高血清高密度脂蛋白-胆固醇水平，同时下调酰基- 辅酶A：胆固醇酰基转移酶-1（ACAT 1）在ApoE-/-小鼠的睾丸中的作用。ACAT 1转化游离胆固醇 转化为胆固醇酯以储存在脂滴中，从而促进动脉粥样硬化病变中的泡沫细胞形成。 体外研究表明，Olfm 2的敲低抑制而Olfm 2的过表达促进脂质过表达。 CCAAT/增强子结合蛋白同源蛋白（CHOP）在氧化型低- 密度脂蛋白处理的SMC。这些数据有力地支持了一个新的假设，即Olfm 2促进 动脉粥样硬化通过介导SMC泡沫细胞的形成和凋亡。使用人体主冠状动脉 SMC、Olfm 2-/-小鼠SMC和SMC谱系追踪Olfm 2-/-小鼠， 组织学和药理学方法，我们将1）测试Olfm 2是否促进SMC泡沫细胞形成， 介导SMC泡沫细胞凋亡; 2）确定Olfm 2在SMC泡沫细胞凋亡中功能的分子机制。 介导SMC泡沫细胞形成和凋亡;和3）确定Olfm 2在SMC泡沫细胞形成和凋亡中的细胞特异性作用。 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 潜在的Olfm 2在动脉粥样硬化形成中的功能，这可能最终导致开发治疗性药物。 在退伍军人和普通人群中对抗动脉粥样硬化的策略。