Targeting smooth muscle cell BMAL1 as a new therapeutic strategy against restenosis

靶向平滑肌细胞 BMAL1 作为抗再狭窄的新治疗策略

• 批准号: 10561398
• 负责人: MING C GONG
• 金额: $ 66.5万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561398
• 关键词: ARNTL gene; Abdominal Aortic Aneurysm; Adopted; Affect; Aging; Aldosterone; Alzheimer' s Disease; American; Angiotensin II; Arachidonic Acids; Arterial Injury; Atherosclerosis; Binding; Biological Assay; Carotid Arteries; Cause of Death; Cell Proliferation; Cells; Clinical Research; Coronary; Coronary Artery Bypass; Coronary artery; Coronary heart disease; Cytosolic Phospholipase A2; Data; Development; Diabetes Mellitus; Endothelial Cells; Enzymes; Female; Genetic; Genetic Transcription; Goals; Hyperplasia; Hypertension; Immune response; Incidence; Injury; Knockout Mice; Lesion; Ligation; Malignant Neoplasms; Mediating; Messenger RNA; Metabolism; Metals; Modality; Molecular; Mus; Pathway Analysis; Patients; Personal Satisfaction; Pharmaceutical Preparations; Platelet-Derived Growth Factor; Proliferating; Reporting; Risk; Role; Scheme; Signal Transduction; Site; Sleep; Smooth Muscle Myocytes; Stents; Testing; Thrombosis; Time; United States; Up-Regulation; Vascular Smooth Muscle; Vascular remodeling; Vascularization; Woman; chromatin immunoprecipitation; circadian pacemaker; cost; femoral artery; insight; loss of function; male; men; mouse model; new therapeutic target; novel therapeutic intervention; novel therapeutics; overexpression; percutaneous coronary intervention; pleiotropism; pre-clinical; promoter; restenosis; stent thrombosis; transcription factor; transcriptome sequencing; vascular inflammation; vascular injury

Project Summary/Abstract Coronary heart disease (CHD) is the single leading cause of death in the United States. Coronary revascularization, including coronary artery bypass graft and percutaneous coronary intervention, is the most common modality in patients with CHD. However, it is often associated with a high incidence of restenosis. Although the rate of restenosis is reduced significantly by using bare-metal stent (BMS) and particularly with drug-eluting stent (DES), a persistently high rate of restenosis after BMS and an increased risk of in-stent thrombosis with DES has been encountered as a major significant gap in the field. The current application proposes to bridge this gap and specifically investigates the role of the smooth muscle cell (SMC) BMAL1 in neointimal hyperplasia in mouse models of arterial injury. BMAL1 is a core molecular component of the circadian clock. It has long been believed that loss of function of BMAL1 is detrimental to well-being. However, this dogma was challenged by our recent report that genetic deletion of Bmal1 in SMCs (SM-Bmal1-KO) protects mice from aldosterone or angiotensin II-induced abdominal aortic aneurysm. Consistent with this finding, our preliminary demonstrate that SMC-specific Bmal1 deletion also protects mice femoral artery wire injury- or carotid artery ligation-induced neointimal hyperplasia. While the underlying mechanism remains elusive, our preliminary data reveal arachidonic acid metabolism is most significantly affected by SMC-specific Bmal1 deletion. Interestingly, among enzymes implicated in arachidonic acid metabolism, cytosolic phospholipase A2 alpha (cPLA2) is most downregulated by SMC-specific Bmal1 deletion. Mechanistically, our preliminary data illustrate that BMAL1 binds to the mouse cPLA2 promoter, and SMC BMAL1 is required for vascular injury-induced cPLA2 upregulation in neointima. Given the potential role of cPLA2 in VSMC proliferation and neointimal hyperplasia, we hypothesize that upregulation of BMAL1 in SMCs by vascular injury promotes cPLA2 expression, thus mediating the initiation and progression of neointimal hyperplasia and significantly contributing to the development of restenosis after coronary revascularization. Aim 1 will test the hypothesis that upregulation of SMC BMAL1 by vascular injury is critical for the onset and progression of neointimal hyperplasia. Aim 2 will define the mechanism by which SMC BMAL1 regulates cPLA2 and thereby mediates vascular injury-induced neointimal hyperplasia. To achieve the goals, SM-Bmal1-KO, SM-cPLA2- KO, and SM-Bmal1/cPLA2-KO mice will be subjected to femoral artery wire injury or carotid artery ligation to induce neointimal hyperplasia and to determine the mechanism by which SMC BMAL1 and cPLA2 mediate vascular injury-induced neointimal hyperplasia. Results from the proposed studies will provide new mechanistic insight on how SMC BMAL1 mediates vascular injury-induced neointimal hyperplasia via cPLA2. Moreover, results from the proposed studies will provide preclinical evidence that inhibiting the BMAL1/cPLA2 signaling at the lesion site is a new therapeutic strategy against restenosis after coronary revascularization.

项目摘要/摘要 冠心病（CHD）是美国的单一主要死亡原因。冠状动脉 血运重建，包括冠状动脉搭桥移植物和经皮冠状动脉干预，是最多的 CHD患者的常见方式。但是，它通常与更高的再狭窄事件有关。 尽管使用裸机支架（BMS），特别是在 药物洗脱支架（DES），BMS后持续高的再狭窄率持续高，并且在内部的风险增加 与DES的血栓形成是该领域的主要显着差距。当前的应用程序 提议弥合这一差距，并专门研究平滑肌细胞（SMC）BMAL1在 动脉损伤小鼠模型中的新内膜增生。 BMAL1是该核心分子成分 昼夜节律。长期以来，人们一直认为，BMAL1功能的丧失对幸福感有害。然而， 我们最近的报告挑战了这一教条，即SMC中BMAL1的遗传缺失（SM-BMAL1-KO） 保护小鼠免受醛固酮或血管紧张素II诱导的腹主动脉瘤的影响。与此一致 发现，我们的初步证明了SMC特异性BMAL1缺失还保护股动脉电线的小鼠 损伤或颈动脉连接引起的新内膜增生。虽然潜在的机制仍然存在 难以捉摸的，我们的初步数据显示，蛛网膜酸代谢受SMC特异性的影响最大 BMAL1删除。有趣的是，在花生四烯酸代谢中实施的酶中，胞质 SMC特异性BMAL1缺失最下调了磷脂酶A2α（CPLA2）。从机械上讲，我们的 初步数据说明BMAL1与鼠标CPLA2启动子结合，并且需要SMC BMAL1。 血管损伤引起的CPLA2新内膜上调。鉴于CPLA2在VSMC中的潜在作用 我们假设血管中BMAL1上调BMAL1的增殖和新内膜增生 损伤促进CPLA2表达，从而介导新蛋白质增生的主动性和进展 AIM 1将测试 假设是通过血管损伤上调SMC BMAL1对于发作和进展至关重要 新内膜增生。 AIM 2将定义SMC BMAL1调节CPLA2的机制 介导血管损伤引起的新内膜增生。为了实现目标，SM-BMAL1-KO，SM-CPLA2-- KO和SM-BMAL1/CPLA2-KO小鼠将遭受股动脉损伤或颈动脉连接 诱导新膜增生并确定SMC BMAL1和CPLA2介导的机制 血管损伤引起的新内膜增生。拟议研究的结果将提供新的机械性 了解SMC BMAL1如何通过CPLA2介导血管损伤引起的新内膜增生。而且， 拟议研究的结果将提供临床前证据，以抑制BMAL1/CPLA2信号传导 在病变部位是一种针对冠状动脉血运重建后再狭窄的新治疗策略。