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

鉴定血管平滑肌细胞 miR-33a 表达的致动脉粥样硬化作用

• 批准号: 10202932
• 负责人: Alexis Stamatikos
• 金额: $ 44.37万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202932
• 关键词: ATP binding cassette transporter 1; Achievement; Aorta; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Cause of Death; Cells; Cessation of life; Cholesterol; Cultured Cells; Development; Disease; Excision; Exhibits; Fatty acid glycerol esters; Foam Cells; Goals; Harvest; Hepatocyte; High Density Lipoproteins; Impairment; In Vitro; Ischemic Stroke; Knowledge; Lead; Lesion; Lipids; Measures; Mediating; Metabolic dysfunction; MicroRNAs; Mus; Myocardial Infarction; Phenotype; Plasma; Play; Population; Process; Proteins; Role; Smooth Muscle Myocytes; Tamoxifen; Testing; United States; Vascular Smooth Muscle; atheroprotective; base; cell type; experimental study; feeding; improved; in vivo; innovation; macrophage; monocyte; mouse model; novel; prevent; protein expression; public health relevance; recombinase-mediated cassette exchange; success; transdifferentiation

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.

项目总结/摘要 动脉粥样硬化是一种由胆固醇在动脉内积聚引起的疾病。运动是 在美国和世界范围内，由于这种疾病是主要原因， 心肌梗塞和缺血性中风的风险。因此，改善动脉粥样硬化的治疗方法可能会大大 减少缺血性中风和心肌梗塞的死亡人数。预防胆固醇 通过增加动脉平滑肌细胞中胆固醇的清除， 一种治疗动脉粥样硬化的潜在策略。动脉平滑肌中胆固醇过量积聚 这些细胞中的miR-33 a表达可能引起细胞内胆固醇的减少，因为miR-33 a促进细胞胆固醇的保留， 因此抑制动脉平滑肌细胞中的miR-33 a可能具有动脉粥样硬化保护作用。这个项目的目标 目的是检测miR-33 a在动脉平滑肌细胞中的表达是否是促动脉粥样硬化的。 有1个体外目标和1个体内目标。体外Aim测试是否在培养的血管中抑制miR-33 a 平滑肌细胞通过增强胆固醇流出来增加胆固醇的去除。体内Aim测试 在血管平滑肌细胞中删除miR-33 a是否会降低脂质含量并减少病变面积， 脂肪喂养的促动脉粥样硬化小鼠模型的动脉粥样硬化。 这两个特定目标的成功将意味着动脉平滑肌细胞内的miR-33 a表达是促血管生成的。 动脉粥样硬化，这至少部分是由于细胞内胆固醇流出减少。因此，成就 这些目标的一部分将证明，在动脉平滑肌细胞中特异性抑制miR-33 a可以 成为治疗动脉粥样硬化的创新方法。

项目成果

miR-33a Expression Attenuates ABCA1-Dependent Cholesterol Efflux and Promotes Macrophage-Like Cell Transdifferentiation in Cultured Vascular Smooth Muscle Cells.

• DOI: 10.1155/2023/8241899
• 发表时间: 2023
• 期刊: JOURNAL OF LIPIDS
• 影响因子: 5.3
• 作者: Esobi, Ikechukwu C.;Oladosu, Olanrewaju;Echesabal-Chen, Jing;Powell, Rhonda R.;Bruce, Terri;Stamatikos, Alexis
• 通讯作者: Stamatikos, Alexis