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.

项目摘要/摘要 动脉粥样硬化是一种疾病，是动脉内胆固醇积累的结果。动脉粥样硬化是 由于这种疾病是主要原因，美国和全球的主要死亡原因是 心肌梗死和缺血性中风。因此，改善动脉粥样硬化的疗法可能会急剧 减少缺血性中风和心肌梗死的死亡人数。预防胆固醇 通过增加动脉平滑肌细胞中胆固醇的去除而在动脉内积聚的IS 治疗动脉粥样硬化的一种潜在策略。在动脉平滑肌中过度胆固醇积累 细胞可能是由miR-33a在这些细胞中的表达引起的，因为miR-33a促进了细胞胆固醇的保留， 因此，抑制动脉平滑肌细胞中的miR-33a可能是动脉保护性的。这个项目的目标 是测试miR-33a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。体外目标测试是否在培养的血管中抑制miR-33a是否抑制miR-33a 平滑肌细胞通过增强胆固醇外排来增加胆固醇的去除。体内目标测试 在血管平滑肌细胞中删除miR-33a是否会降低脂质含量并降低病变区域 脂肪喂养的促动物源性小鼠模型的主动脉。 两种特定目标的成功都将暗示动脉平滑肌细胞内的miR-33a表达 动脉粥样硬化，这至少部分是由于细胞内胆固醇外排的降低。因此，成就 这些目的将表明概念概念表明，在动脉平滑肌细胞中抑制miR-33a可能 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