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

基本信息

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
项目类别：
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

项目摘要

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导致的并发症，包括心肌尽管经过数十年的研究，梗塞和中风仍然是全球死亡的主要原因。导致斑块破裂的因素仍知之甚少，普遍认为病变具有高光滑度。肌细胞 (SMC) 与巨噬细胞 (Mφ) 的比例不太可能破裂，但在动脉粥样硬化的情况下，SMC 破裂的可能性较小。下调其特征标记并表达其他细胞类型的标记，因此无法使用事实上，我们的实验室使用 Myh11 ERT2Cre eYFP ApoE-/- 小鼠进行了严格的 SMC 谱系追踪研究。研究表明，病变内 80% 以上的 SMC 缺乏先前用于识别的标记物的表达并且这些细胞中近 30% 激活了 Mφ 的多个标记，因此，其中 SMC 的数量。病变不仅被严重低估，而且许多被认为是 M 的细胞实际上是 SMC 衍生的。更重要的是，我们发现干细胞多能性基因 Klf4 和 SMC 特异性条件敲除 Oct4 对病变的发病机制具有深远的影响，包括斑块稳定性多个指标的改变。然而，与 SMC 始终具有动脉粥样硬化保护作用的教条相反，我们证明它们可以是综上所述，研究表明它们具有保护性或促进性，具体取决于其表型转变的性质。强调确定促进 SMC 表型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中白细胞介素 1 的中和作用。总体假设是炎症会导致动脉粥样硬化，抑制炎症会改善动脉粥样硬化然而，缺乏临床前证据表明 IL1 的中和会带来有益的效果。事实上，我们实验室（包括申请人）最近的研究表明，在晚期动脉粥样硬化的情况下。在使用诺华 IL1 中和抗体对 Myh11 ERT2Cre eYFP ApoE-/- 小鼠进行治疗后晚期动脉粥样硬化的形成导致了与斑块稳定性降低一致的多种变化包括纤维帽内 SMC 衍生的 eYFP+ 细胞数量显着减少，以及替换本提案中的研究将检验 SMC 中的 IL1 信号传导对于细胞增殖至关重要的假设。维持晚期动脉粥样硬化斑块的稳定性目标 1 检验以下假设：针对晚期动脉粥样硬化的抗 IL1 Ab 治疗主要通过 SMC 中的 IL1R1 信号介导，并且这会导致病变 SMC 发生有害的表型转变。目标 2 将检验产量增加的假设。抗 IL1 Ab 治疗患有晚期病变的 Myh11 ERT2Cre eYFP ApoE-/- 小鼠后白细胞介素 4 (IL4) 的变化有助于抗 IL1 Ab 治疗对我们最初观察到的晚期病变发病机制的有害影响这些研究将大大增加我们对晚期动脉粥样硬化中 IL1 信号传导的了解，并可能确定增强当前疗法的方法，以促进 SMC 表型的动脉粥样硬化变化，以及最终改善患者的治疗效果。