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： 钙化性主动脉瓣疾病 (CAVD) 是主动脉瓣狭窄最常见的原因，影响 25% 65 岁以上的人进展为有症状的严重主动脉瓣狭窄。 如果不通过手术或经导管主动脉瓣置换术 (TAVR) 进行治疗，2 年内死亡率可达 50%。 目前，尚无预防或治疗这种 CAVD 的药物疗法，而且可以进行手术。 对于许多患有多种合并症的老年患者来说，这是一种高风险的手术。 在钙化的进展中发挥关键作用，并可能具有开发第一种治疗方法的潜力 然而，炎症钙化的潜在机制却很少。 我们的实验室已经开始定义一种对进展至关重要的新型炎症信号通路。 我们确定了高胆固醇血症模型中的血管钙化是巨噬细胞 Rac1 依赖性的。 炎症细胞因子白介素-1β (IL-1β) 的表达是进行性动脉粥样硬化所必需的 巨噬细胞 Rac1 介导的 IL-1β 表达的作用从未在模型中得到评估。 本提案中提出的未发表的初步数据表明，这一点。 在符合以下条件的情况下，Rac1 诱导的巨噬细胞中 IL-1β 表达可以上调 高胆固醇血症诱导的 CAVD。使用基于高脂血症的小鼠模型 (ApoE-/-) 进行 CAVD 和 诱导型巨噬细胞 Rac1 缺失 (CSF1RmcmRac1fl/fl)，我们在初步研究中观察到 CAVD 的发展依赖于巨噬细胞特异性 Rac1 信号传导。 对于主动脉瓣狭窄，包括血流速度和瓣膜面积升高，在小鼠中 巨噬细胞 Rac1 的诱导性基因缺失对瓣膜的组织学评估表明减少。 Rac1 缺失的巨噬细胞中瓣膜厚度、瓣膜钙化减少和纤维化减少 此外，我们观察到 Rac1 缺失的巨噬细胞中循环（血清）IL-1β 水平降低。 我们小组之前的工作表明IL-1β促进骨形成的成骨转录。 因子表达，与巨噬细胞 Rac 依赖性血管钙化密切相关 考虑到巨噬细胞 Rac1 对 CAVD 发展的观察，它与 IL-1β 相关。 以及过去关于 IL-1β 对体外钙化的贡献的研究结果，我们发现巨噬细胞 特定的 Rac1-IL-1β 信号通路是驱动炎症进展的关键机制 CAVD 对严重主动脉瓣狭窄的具体目标是确定 Rac1 的个体作用。 活性和 IL-1β 在促进 CAVD 和随后的体内主动脉瓣狭窄中的作用。 CAVD 的机制对于开发旨在破坏 CAVD 的新型治疗干预措施至关重要 疾病的自然病程。