Macrophage Rac1 Signaling is required for the progression of Calcific Aortic Valve Disease and consequent Aortic Valve Stenosis

钙化性主动脉瓣疾病和随后的主动脉瓣狭窄的进展需要巨噬细胞 Rac1 信号传导

• 批准号: 9758454
• 负责人: Joshua Berus
• 金额: $ 4.5万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9758454
• 关键词: Address; Affect; Age-Years; Aging; Animal Model; Animals; Aortic Valve Stenosis; Area; Arterial Fatty Streak; Automobile Driving; Blood Flow Velocity; Comorbidity; Coronary Arteriosclerosis; Critical Pathways; Dangerousness; Data; Development; Disease; Disease Progression; Echocardiography; Elderly; Failure; Fibrosis; Gene Deletion; Generations; Genes; Goals; Guanosine Triphosphate; Heart failure; Histologic; Histology; Hydroxymethylglutaryl-CoA reductase; Hyperlipidemia; Imaging Techniques; In Vitro; Individual; Inflammatory; Inflammatory Response; Interleukin-1 beta; Knowledge; Laboratories; Lead; Left; Lipids; Measures; Mediating; Medical; Mentors; Microscopy; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mus; Operative Surgical Procedures; Pathway interactions; Patients; Physiological; Play; Population; Prevention; Prevention therapy; Procedures; Process; Research; Risk Factors; Role; Serum; Signal Pathway; Signal Transduction; Sudden Death; System; Testing; Therapeutic; Thick; Tissues; Vascular calcification; Work; age related; aortic valve; aortic valve disorder; aortic valve replacement; baby boomer; base; bone; calcification; cytokine; end stage disease; ex vivo imaging; high risk; human old age (65+); hypercholesterolemia; in vivo; knock-down; macrophage; mortality; mouse model; novel; novel therapeutic intervention; older patient; osteogenic; prevent; risk sharing; targeted treatment; therapeutic target; transcription factor; treatment strategy; valve replacement

ABSTRACT: Calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis, affecting 25% of people over the age of 65 years. Patients who progress to symptomatic, severe aortic valve stenosis have a 50% mortality within 2 years if left untreated by surgical or transcatheter aortic valve replacement (TAVR). Currently, there is no medical therapy for the prevention or treatment of this CAVD. Moreover, surgery can be a high-risk procedure for many older patients with multiple comorbidities. Inflammatory signaling appears to play a key role in progression of calcification and may hold the potential to develop the first therapeutic treatment of CAVD. However, the underlying mechanisms of inflammatory calcification are minimally understood. Our laboratory has begun defining a novel inflammatory signaling pathway critical to progressive vascular calcification in models of hypercholesterolemia. We determined macrophage Rac1-dependent expression of the inflammatory cytokine, interleukin-1β (IL-1β), is required for progressive atherosclerotic calcification. The role of macrophage Rac1-mediated IL-1β expression has never been evaluated in models of calcific aortic valve disease. Unpublished preliminary data presented in this proposal demonstrates that this Rac1-induced IL-1β expression can be upregulated in macrophages under conditions consistent with hypercholesterolemia-induced CAVD. Using a hyperlipidemia-based mouse model (ApoE-/-) for CAVD and an inducible macrophage Rac1-deletion (CSF1RmcmRac1fl/fl), we observed in a preliminary study that the development of CAVD was dependent on macrophage-specific Rac1 signaling. Echocardiographic measures for aortic valve stenosis, including elevated blood flow velocity and valve area, were decreased in mice after inducible gene-deletion of macrophage Rac1. Histological assessment of the valve demonstrated reduced valve thickness, decreased valve calcification and decreased fibrosis in the macrophage Rac1-deleted animals. Moreover, we observed reduced circulating (serum) IL-1β levels in the macrophage Rac1-deleted animals. Our group's previous work has indicated that IL-1β promotes bone-forming osteogenic transcription factor expression and is strongly associated with vascular calcification in a macrophage Rac-dependent manner. Considering observations of macrophage Rac1 on CAVD development, it's association with IL-1β, and past findings on the contribution of IL-1β to calcification in vitro, we hypothesize that a macrophage- specific Rac1-IL-1β signaling pathway is a critical inflammatory mechanism that drives the progression of CAVD to severe aortic valve stenosis. Our specific aims are to determine the individual roles of both Rac1 activity and IL-1β in the promotion of CAVD and consequent aortic valve stenosis in vivo. Defining mechanisms of CAVD is critical to the development of novel therapeutic interventions aimed at disrupting the natural course of the disease.

抽象的： 钙化主动脉瓣疾病（CAVD）是主动脉狭窄的最常见原因，影响了25％ 65岁以上的人。发展为有症状，严重主动脉瓣狭窄的患者患有 如果未经手术或经导管主动脉瓣置换（TAVR）未治疗，则在2年内50％死亡率。 目前，没有用于预防或治疗该CAVD的药物疗法。而且，手术可以是 许多合并症的老年患者是一种高风险手术。炎症信号传导似乎 在计算进展中起关键作用，并可能具有开发第一种疗法的潜力 CAVD的处理。但是，炎症计算的潜在机制是最小的 理解。我们的实验室已经开始定义一种新颖的炎症信号通路，至关重要 高胆固醇血症模型中的血管计算。我们确定了巨噬细胞Rac1依赖性 进行性动脉粥样硬化需要炎性细胞因子白细胞因子1β（IL-1β）的表达 钙化。巨噬细胞Rac1介导的IL-1β表达的作用从未在模型中评估过 钙化主动脉瓣疾病。本提案中提出的未发表的初步数据表明这一点 Rac1诱导的IL-1β表达可以在巨噬细胞中进行更新 高胆固醇血症引起的CAVD。使用基于高脂血症的鼠标模型（APOE-/ - ）用于CAVD和 诱导巨噬细胞Rac1-局部（CSF1RMCMRAC1FL/FL），我们在一项初步研究中观察到 CAVD的发展取决于巨噬细胞特异性的Rac1信号传导。超声心动图测量 对于主动脉瓣狭窄，包括升高的血流速度和瓣膜区域，在小鼠中减少了 巨噬细胞Rac1的诱导基因删除。阀门的组织学评估显示出降低 气门厚度，阀门计算减少和巨噬细胞降低的纤维化。 动物。此外，我们观察到巨噬细胞Rac1删除的循环（血清）IL-1β水平降低 动物。我们小组以前的工作表明IL-1β促进了骨形成的成骨转录 因子表达，与巨噬细胞依赖性的血管计算密切相关 方式。考虑到巨噬细胞Rac1对CAVD发育的观察，它与IL-1β的关联， 以及过去关于IL-1β在体外钙化的贡献的发现，我们假设巨噬细胞 - 特定的Rac1-IL-1β信号通路是一种关键的炎症机制，可驱动 CAVD到严重的主动脉瓣狭窄。我们的具体目的是确定两个Rac1的个体角色 在促进CAVD和随之而来的主动脉瓣狭窄中的活性和IL-1β。定义 CAVD机制对于开发新型治疗干预措施至关重要，旨在破坏这种干预措施 自然病程。