Identifying an Atherogenic Role for Vascular Smooth Muscle Cell miR-33a Expression

项目摘要/摘要 动脉粥样硬化是一种胆固醇在动脉内积聚的疾病。动脉粥样硬化是 这种疾病是美国和世界范围内的主要死亡原因 心肌梗死和缺血性中风。因此，改进动脉粥样硬化的治疗方法可能会大大 减少因缺血性中风和心肌梗塞而死亡的人数。预防胆固醇 通过增加动脉平滑肌细胞中胆固醇的清除而在动脉内蓄积 治疗动脉粥样硬化的一种潜在策略。动脉平滑肌中胆固醇的过度蓄积 这些细胞可能是由miR-33a的表达引起的，因为miR-33a促进了细胞胆固醇的滞留， 因此，抑制动脉平滑肌细胞中的miR-33a可能具有动脉粥样硬化保护作用。这个项目的目标是 目的是测试miR-33a在动脉平滑肌细胞中的表达是否促进动脉粥样硬化。 有1个体外靶点和1个体内靶点。体外AIM检测是否抑制培养的血管miR-33a 平滑肌细胞通过促进胆固醇外流来增加胆固醇的排出。体内AIM试验 血管平滑肌细胞miR-33a缺失是否可降低脂质含量，缩小病变面积 脂肪喂养致动脉粥样硬化的小鼠模型的动脉。 这两个目标的成功将意味着动脉平滑肌细胞中miR-33a的表达是有利的。 导致动脉粥样硬化，这至少部分是由于减少了细胞内胆固醇的外流。因此，成就 在这些目的中，将显示概念证明，在动脉平滑肌细胞中特异性地抑制miR-33a可能 是治疗动脉粥样硬化的一种创新方法。

PROJECT SUMMARY/ABSTRACT Atherosclerosis is a disease that is the result of cholesterol accumulating within arteries. Atherosclerosis is the leading cause of death both within the United States and worldwide due to this disease being the primary cause of myocardial infarctions and ischemic strokes. Therefore, improving therapies for atherosclerosis may drastically decrease the number of deaths from ischemic strokes and myocardial infarctions. Preventing cholesterol accumulation within arteries via increasing the removal of cholesterol in the smooth muscle cells of arteries is one potential strategy to treat atherosclerosis. Excessive cholesterol accumulation in arterial smooth muscle cells may be caused by miR-33a expression in these cells, since miR-33a promotes cellular cholesterol retention, and therefore inhibiting miR-33a in arterial smooth muscle cells may be atheroprotective. The goal of this project is to test whether miR-33a expression in arterial smooth muscle cells is pro-atherogenic. There is 1 in vitro Aim and 1 in vivo Aim. The in vitro Aim tests whether inhibiting miR-33a in cultured vascular smooth muscle cells increases the removal of cholesterol via enhancing cholesterol efflux. The in vivo Aim tests whether deleting miR-33a in vascular smooth muscle cells decreases lipid content and reduces lesion area within the aortas of fat-fed pro-atherogenic mouse models. Success with both Specific Aims will imply that miR-33a expression within arterial smooth muscle cells is pro- atherogenic and this is at least partially due to decreasing intracellular cholesterol efflux. Therefore, achievement of these Aims will show proof-of-concept that inhibiting miR-33a specifically in arterial smooth muscle cells may be an innovative approach to treating atherosclerosis.