Novel Mechanisms Underlying the Development of Atherosclerosis

项目摘要 冠状动脉粥样硬化是导致美国退伍军人心血管住院的五大原因之一。 动脉粥样硬化是一种复杂的进展性疾病，其特征是由脂类组成的斑块堆积。 动脉内膜有丰富的泡沫细胞、炎性细胞和纤维成分。动脉粥样硬化与 急性心肌梗塞、心力衰竭和中风的高风险，这是前五大原因中的另外三个 用于退伍军人心血管住院治疗。已有研究表明血管平滑肌细胞(SMC)和 核因子-kB信号参与动脉粥样硬化的发生发展。然而， 在动脉粥样硬化中，调控SMC功能的因素和机制在很大程度上仍不清楚。我们激动人心的 初步数据表明，嗅觉内酯2(Olfm2)在肿瘤的发生发展中起着重要的作用。 动脉硬化。在SMC泡沫细胞形成过程中，OLFM2在脂质负载的SMC中被诱导，在小鼠和 人类动脉粥样硬化病变。重要的是，Olfm2缺乏(Olfm2-/-)抑制了高脂饮食诱导的 动脉粥样硬化晚期斑块的形成和改善斑块的稳定性。在生物化学方面， Olfm2-/-升高血清高密度脂蛋白-胆固醇水平，下调酰基-胆固醇的表达 ApoE-/-小鼠主动脉中辅酶A：胆固醇酰基转移酶-1(ACAT1)的表达ACAT1转化游离胆固醇 转化为胆固醇酯，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基因的敲除抑制作用，而Olfm2基因的过表达则促进血脂。 氧化低密度脂蛋白中CCAAT/增强子结合蛋白同源蛋白的积累和表达 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Olfm2促进 通过介导SMC泡沫细胞的形成和凋亡而导致动脉粥样硬化。利用原代人冠状动脉 SMCs、Olfm2-/-小鼠SMCs和SMC谱系追踪Olfm2-/-小鼠与分子、细胞、 组织学和药理学方法，我们将1)测试Olfm2是否促进SMC泡沫细胞的形成和 介导SMC泡沫细胞的凋亡；2)确定Olfm2功能的分子机制 介导SMC泡沫细胞的形成和凋亡；以及3)确定Olfm2在SMC中的细胞特异性作用。 活体动脉粥样硬化。拟议研究的成功完成将揭开一种新的机制 潜在的Olfm2在动脉粥样硬化形成中的作用，这可能最终导致治疗性 在退伍军人和普通人群中对抗动脉粥样硬化的策略。

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.