IL1β Promotes Atheroprotective Changes in Late Stage Atherosclerotic Lesions

IL1β 促进晚期动脉粥样硬化病变的动脉粥样硬化变化

• 批准号: 9395309
• 负责人: Richard Baylis
• 金额: $ 3.15万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2021-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9395309
• 关键词: Antibodies; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; CCL2 gene; Cardiovascular system; Cause of Death; Cell Lineage; Cell Proliferation; Cells; Cessation of life; Characteristics; Clinical Trials; Coculture Techniques; Coronary; Data; Endothelial Cells; Event; Exhibits; Genes; Goals; Human; IL1R1 gene; Immunoglobulin G; In Vitro; Incidence; Inflammation; Inflammatory; Interleukin 4 Receptor; Interleukin-1; Interleukin-1 beta; Interleukin-4; Knock-out; Lesion; Lesion by Morphology; Lesion by Stage; Maintenance; Mediating; Mus; Myocardial Infarction; Nature; Pathogenesis; Patient-Focused Outcomes; Patients; Phase III Clinical Trials; Phenotype; Play; Postdoctoral Fellow; Production; Protein Isoforms; Proteins; Recruitment Activity; Recurrence; Research; Research Proposals; Role; Rupture; Secondary to; Signal Transduction; Smooth Muscle Myocytes; Stem cells; Stroke; Testing; Therapeutic; Thick; Transgenes; atheroprotective; atherothrombosis; cardiovascular risk factor; cell type; cytokine; design; feeding; high risk; improved; indexing; macrophage; monocyte; mouse model; neutralizing antibody; pluripotency; pre-clinical; promoter; stroke treatment; vascular smooth muscle cell proliferation; western diet

PROJECT SUMMARY: Complications resulting from rupture of unstable atherosclerotic lesions, including myocardial infarction and stroke, are the leading cause of death worldwide. Despite decades of research, the mechanisms and factors leading to plaque rupture remain poorly understood. It is generally accepted that lesions with a high smooth muscle cell (SMC) to macrophage (Mϕ) ratio are less likely to rupture. However in the setting of atherosclerosis, SMC down-regulate their characteristic markers and express markers of other cells types and thus are undetectable using traditional markers. Indeed, rigorous SMC lineage tracing studies by our lab using Myh11 ERT2Cre eYFP ApoE-/- mice have shown that >80% of SMC within lesions lack expression of the markers previously used for their identification and that nearly 30% of these cells have activated multiple markers of Mϕ. Therefore, the number of SMC within lesions has not only been grossly underestimated, but many cells thought to be Mϕ are actually SMC-derived. Of even greater significance, we showed that SMC-specific conditional knockout of the stem cell pluripotency genes Klf4 and Oct4 had a profound impact on the pathogenesis of lesions including alterations in multiple indices of plaque stability. However, contrary to the dogma that SMC are always atheroprotective, we showed they can be either atheroprotective or -promoting depending on the nature of their phenotypic transitions. Taken together, studies highlight the importance of identifying factors and mechanisms that promote beneficial changes in SMC phenotype. An ongoing clinical trial is investigating neutralization of interleukin-1 in high-risk cardiovascular patients. The overarching hypothesis is that inflammation drives atherosclerosis, and that inhibition of inflammation will improve patient survival. However, there is a lack of preclinical evidence that neutralization of IL1 will confer beneficial effects in the setting of advanced atherosclerosis. Indeed, recent studies from our lab, which included the applicant, showed that treatment of our Myh11 ERT2Cre eYFP ApoE-/- mice with the Novartis IL1-neutralizing antibody after the establishment of advanced atherosclerosis resulted in multiple changes consistent with reduced plaque stability including marked reductions in the number of SMC-derived eYFP+ cells within the fibrous cap, and replacement of these cells with Mϕ. Studies in this proposal will test the hypothesis that IL1 signaling in SMC is critical for maintenance of plaque stability in late-stage atherosclerosis. Aim 1 test the hypothesis that the detrimental effects of anti-IL1 Ab treatment on late-stage atherosclerosis are primarily mediated through IL1R1 signaling in SMC and that this results in deleterious phenotypic transitions in lesion SMC. Aim 2 will test the hypothesis that increased production of interleukin-4 (IL4) following anti-IL1 Ab treatment of Myh11 ERT2Cre eYFP ApoE-/- mice with advanced lesions contributes to the deleterious effects of anti-IL1 Ab treatment on late-stage lesion pathogenesis observed in our initial studies. These studies will greatly increase our understanding of IL1 signaling in late-stage atherosclerosis and may identify approaches to augment current therapies to promote atheroprotective changes in SMC phenotypes and ultimately improve patient outcomes.

项目摘要：不稳定动脉粥样硬化病变破裂引起的并发症，包括心肌 梗塞和中风是全球死亡的主要原因。尽管进行了数十年的研究，机制和 导致斑块破裂的因素仍然很少了解。人们普遍认为，光滑的病变 肌肉细胞（SMC）与巨噬细胞（Mϕ）的比率不太可能破裂。但是，在动脉粥样硬化的情况下 下调其特征标记和其他类型的表达标记，因此无法使用 传统标记。确实，我们的实验室使用MyH11 ERT2CRE EYFP APOE - / - 小鼠进行了严格的SMC谱系跟踪研究 已经表明，病变内的SMC> 80％缺乏以前用于识别的标记物的表达 这些细胞中几乎有30％激活了M ϕ的多个标记。因此，内部的SMC数 病变不仅被严重低估了，而且许多被认为是M ϕ的细胞实际上是SMC衍生的。偶数 更大的意义，我们表明了干细胞多能基因KLF4和 OCT4对病变的发病机理有深远的影响，包括改变斑块稳定性的多种指数。 但是，与SMC始终是动脉保护的教条形成鲜明对比，我们表明它们可以是 动脉保护性或促进性取决于其表型过渡的性质。总的来说，研究 强调识别促进SMC表型中有益变化的因素和机制的重要性。 一项正在进行的临床试验正在研究高危心血管患者白介素-1的神经化。这 总体假设是注射驱动动脉粥样硬化，并且对注射的抑制作用将改善 患者生存。但是，缺乏临床前证明IL1的中和会带来有益的效果 确实，我们的实验室的最新研究（包括申请人）显示 使用NovartisIL1-中和抗体的MYH11 ERT2CRE EYFP APOE - / - 小鼠的处理 高级动脉粥样硬化的建立导致多种变化，这与斑块稳定性降低一致 包括纤维帽内SMC衍生的EYFP+细胞数量的明显减少，并更换 这些带有M ϕ的细胞。该提案中的研究将检验以下假设：SMC中的IL1信号传导至关重要 维持晚期动脉粥样硬化的斑块稳定性。 AIM 1检验以下假设： 晚期动脉粥样硬化的抗IL1AB治疗主要是通过SMC中的IL1R1信号传导介导的 这导致病变SMC中有害的表型转变。 AIM 2将测试增加产量的假设 抗IL1AB治疗MyH11 ERT2CRE EYFP APOE - / - 带有晚期病变的抗IL1AB处理后的白介素-4（IL4） 有助于抗IL1AB处理对我们初始观察到的晚期病变发病机理的有害作用 研究。这些研究将大大增加我们对后期动脉粥样硬化中IL1信号传导的理解，可能 确定增加当前疗法的方法，以促进SMC表型和 最终改善患者的预后。