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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要/摘要冠心病（CHD）是美国唯一的主要死亡原因。血运重建，包括冠状动脉旁路移植术和经皮冠状动脉介入治疗，是目前最有效的治疗方法。 CHD 患者的常见治疗方式，但通常与再狭窄的高发生率相关。尽管使用裸金属支架 (BMS) 可以显着降低再狭窄率，特别是使用药物洗脱支架 (DES)、BMS 后再狭窄率持续较高以及支架内风险增加 DES 的血栓形成已成为当前应用领域的一个重大空白。 Bridge 提出了这一空白，并专门研究了平滑肌细胞 (SMC) BMAL1 在小鼠动脉损伤模型中的新生内膜增生是 BMAL1 的核心分子成分。长期以来，人们一直认为 BMAL1 功能的丧失会影响健康。我们最近的报告挑战了这一教条，即 SMC 中 Bmal1 基因缺失 (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。我们初步证明 SMC 特异性 Bmal1 缺失也能保护小鼠股动脉线损伤或颈动脉结扎引起的新内膜增生，而潜在的机制仍然存在。虽然难以捉摸，但我们的初步数据显示花生四烯酸代谢受 SMC 特异性影响最为显着在与花生四烯酸代谢有关的酶中，Bmal1 被提示删除。从机制上讲，SMC 特异性 Bmal1 缺失对磷脂酶 A2 α (cPLA2α) 的下调最为明显。初步数据表明 BMAL1 与小鼠 cPLA2 启动子结合，并且 SMC BMAL1 是鉴于 cPLA2α 在 VSMC 中的潜在作用，血管损伤诱导的 cPLA2α 上调。增殖和新内膜增生，我们通过血管对 SMC 中 BMAL1 的上调进行了研究损伤促进cPLA2α表达，从而介导新内膜增生和目标 1 将测试假设血管损伤导致 SMC BMAL1 的上调对于疾病的发生和进展至关重要目标 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小鼠将受到股动脉线损伤或颈动脉结扎以诱导内膜增生并确定 SMC BMAL1 和 cPLA2 介导的机制血管损伤引起的新内膜增生的研究结果将提供新的机制。深入了解 SMC BMAL1 如何通过 cPLA2 介导血管损伤诱导的内膜增生。拟议研究的结果将提供抑制 BMAL1/cPLA2 信号传导的临床前证据在病变部位进行治疗是对抗冠状动脉血运重建后再狭窄的一种新的治疗策略。