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.

项目总结：不稳定动脉粥样硬化病变破裂导致的并发症，包括心肌 梗塞和中风是世界范围内的主要死亡原因。尽管经过几十年的研究， 导致斑块破裂的因素仍然知之甚少。通常认为，具有高光滑度的病变 肌肉细胞（SMC）与巨噬细胞（M+）的比率较不可能破裂。然而，在动脉粥样硬化的情况下，SMC 下调它们的特征性标志物并表达其他细胞类型的标志物，因此使用 传统的标记。事实上，我们实验室使用Myh 11 ERT 2Cre eYFP ApoE-/-小鼠进行的严格SMC谱系追踪研究 已经表明，病变内>80%的SMC缺乏先前用于其鉴定的标记物的表达 并且这些细胞中有近30%激活了多个M β标记。因此， 病变不仅被严重低估，而且许多被认为是M细胞的细胞实际上是SMC衍生的。甚至 更重要的是，我们发现SMC特异性条件性敲除干细胞多能性基因Klf 4和Klf 6， Oct 4对病变的发病机制有深远的影响，包括斑块稳定性的多个指标的改变。 然而，与SMC总是具有动脉粥样硬化保护作用的教条相反，我们发现它们可以是 动脉粥样硬化保护或促进，这取决于其表型转变的性质。综合来看，研究 强调识别促进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。的 总体假设是炎症驱动动脉粥样硬化，并且抑制炎症将改善动脉粥样硬化。 患者生存率。然而，缺乏临床前证据表明IL 1 β的中和将赋予有益的作用 在晚期动脉粥样硬化的情况下。事实上，我们实验室最近的研究，包括申请人，显示 我们的Myh 11 ERT 2Cre eYFP ApoE-/-小鼠用Novartis IL 1 β-中和抗体治疗后， 晚期动脉粥样硬化的建立导致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+细胞数量的显著减少，以及 这些细胞与M β。本研究将验证SMC中IL 1 β信号传导对细胞凋亡至关重要的假设。 在晚期动脉粥样硬化中维持斑块稳定性。目的1检验以下假设： 抗IL 1 β Ab治疗晚期动脉粥样硬化主要通过SMC中的IL 1 R1信号传导介导， 这导致损伤SMC中有害的表型转变。目标2将检验增产的假设， Myh 11 ERT 2Cre eYFP ApoE-/-小鼠晚期病变后抗IL-1 β Ab治疗的白细胞介素-4（IL-4） 有助于抗IL-1 β Ab治疗对晚期病变发病机制的有害作用， 问题研究这些研究将大大增加我们对动脉粥样硬化晚期IL 1 β信号的理解， 确定增强当前治疗的方法，以促进SMC表型中的动脉粥样硬化保护性变化， 最终改善患者的预后。