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）住院的五个主要原因之一。 动脉粥样硬化是一种复杂而进行的疾病，其特征是由脂质组成的斑块积聚 动脉内膜中的富泡沫细胞，炎性细胞和纤维元素。动脉粥样硬化与 急性心肌梗塞，心力衰竭和中风的高风险，这是前五名的另外三个原因 用于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展和进展。但是， 在动脉粥样硬化中控制SMC功能的因素和机制仍然很大未知。我们令人兴奋 初步数据表明嗅觉素2（OLFM2）在发展中起着至关重要的作用 动脉粥样硬化。在SMC泡沫细胞形成和小鼠和小鼠和 人动脉粥样硬化病变。重要的是，OLFM2缺乏症（OLFM2 - / - ）抑制了高脂肪饮食引起的 动脉粥样硬化的斑块形成并改善了晚期动脉粥样硬化的斑块稳定性。生化， OLFM2 - / - 提高了高密度脂蛋白 - 胆固醇的血清水平，而下调了酰基的表达 辅酶A：APOE-/ - 小鼠主动脉中的胆固醇酰基转移酶-1（ACAT1）。 ACAT1转换免费胆固醇 进入胆固醇酯以在脂质液滴中储存，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，OLFM2的敲低抑制了OLFM2的过表达可促进脂质 氧化的低 - 密度脂蛋白处理的SMC。这些数据强烈支持OLFM2促进的新假设 通过介导SMC泡沫细胞的形成和凋亡，动脉粥样硬化。使用原发性冠状动脉 SMC，OLFM2 - / - 小鼠SMC和SMC谱系追踪OLFM2 - / - 小鼠与分子，细胞，细胞， 组织学和药理方法，我们将测试OLFM2是否促进了SMC泡沫细胞的形成和 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在细胞中的作用 动脉粥样硬化在体内。成功完成拟议的研究将揭示新的机制 动脉粥样硬化中的基本OLFM2功能，这可能最终导致治疗的发展 在退伍军人和一般人群中针对动脉粥样硬化的策略。