IL1beta signaling in SMCpromotes beneficial changes in late stage atherosclerotic lesion pathogenesis

SMC 中的 IL1β 信号传导促进晚期动脉粥样硬化病变发病机制的有益变化

• 批准号: 10331329
• 负责人: Gary K Owens
• 金额: $ 76.87万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331329
• 关键词: Address; Anti-Inflammatory Agents; Antibodies; Antibody Therapy; Apolipoprotein E; Applications Grants; Arterial Fatty Streak; Atherosclerosis; Attenuated; Blood Vessels; Cause of Death; Cell Lineage; Cells; Clinical; Clinical Trials; Collagen; Coronary Arteriosclerosis; Coronary artery; Development; Disease Resistance; Elderly; Extracellular Matrix; Genes; Genomics; Heart failure; Human; Hyperlipidemia; IL1R1 gene; Immunoglobulin G; Impairment; Inflammation; Inflammatory; Interleukin-1 beta; Intervention; Investments; Knock-out; Lesion; Lesion by Stage; Life Style Modification; Ligands; Lipids; Maintenance; Medicine; Microscopic; Mus; Myocardial Infarction; Nature; Necrosis; Outcome; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Process; Resolution; Role; Rupture; Signal Transduction; Site; Smooth Muscle Myocytes; Stem cell pluripotency; Stimulus; Tamoxifen; Testing; Therapeutic; Thick; Thinness; Tissues; atheroprotective; atherothrombosis; biomarker panel; cardiovascular disorder risk; cell type; chronic inflammatory disease; cohort; conditional knockout; effective therapy; expectation; feeding; healing; improved; indexing; injury and repair; insight; macrophage; neutralizing antibody; pathogen; premature; prevent; receptor; response; trafficking; western diet; Address; Anti-Inflammatory Agents; Antibodies; Antibody Therapy; Apolipoprotein E; Applications Grants; Arterial Fatty Streak; Atherosclerosis; Attenuated; Blood Vessels; Cause of Death; Cell Lineage; Cells; Clinical; Clinical Trials; Collagen; Coronary Arteriosclerosis; Coronary artery; Development; Disease Resistance; Elderly; Extracellular Matrix; Genes; Genomics; Heart failure; Human; Hyperlipidemia; IL1R1 gene; Immunoglobulin G; Impairment; Inflammation; Inflammatory; Interleukin-1 beta; Intervention; Investments; Knock-out; Lesion; Lesion by Stage; Life Style Modification; Ligands; Lipids; Maintenance; Medicine; Microscopic; Mus; Myocardial Infarction; Nature; Necrosis; Outcome; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Process; Resolution; Role; Rupture; Signal Transduction; Site; Smooth Muscle Myocytes; Stem cell pluripotency; Stimulus; Tamoxifen; Testing; Therapeutic; Thick; Thinness; Tissues; atheroprotective; atherothrombosis; biomarker panel; cardiovascular disorder risk; cell type; chronic inflammatory disease; cohort; conditional knockout; effective therapy; expectation; feeding; healing; improved; indexing; injury and repair; insight; macrophage; neutralizing antibody; pathogen; premature; prevent; receptor; response; trafficking; western diet

Atherothrombosis, resulting from rupture or erosion of unstable atherosclerotic plaques, is the leading cause of death worldwide. However, the mechanisms that regulate the stability of late stage atherosclerotic lesions remain poorly understood. The dogma is that: 1) plaques containing a large necrotic core, a thin fibrous cap, and large numbers of CD68+ cells relative to Acta2+ cells [presumed to be macrophages (MФ) and smooth muscle cells (SMC) respectively] are more prone to rupture; and 2) SMC play a beneficial role because they are the primary cell type responsible for formation of a matrix-rich protective fibrous cap. However, recent studies by our lab involving simultaneous SMC lineage tracing and SMC-specific knockout (KO) of the stem cell pluripotency genes Oct4 or Klf4, provide compelling evidence challenging this dogma including showing that SMC can have major beneficial or detrimental effects on late stage lesion pathogenesis depending on the nature of their phenotypic transitions. As such, we sought to identify mechanisms to promote beneficial (atheroprotective) SMC phenotypic transitions, and hypothesized that treatment with an anti-IL1β antibody (Ab) to globally suppress inflammation would induce such changes. However, completely contrary to expectations, treatment of our SMC lineage-tracing ApoE-/- mice with the anti-IL1β Ab between 18-26 weeks of Western diet resulted in multiple detrimental changes including a marked reduction in fibrous cap thickness and collagen content, rapid loss of fibrous cap SMC and replacement with MФs, and impaired outward remodeling. Studies in this proposal will test the hypothesis that that IL1β signaling in SMC plays a critical beneficial role in late stage lesion pathogenesis including being required for formation and maintenance of a protective fibrous cap. Aim 1 will determine if persistent IL1R1 signaling within SMC is required for maintenance of a SMC rich fibrous cap. Studies will include determining the contributions of each of the IL1R1 ligands IL1β, and IL1α, as well as IL1Ra. We will also determine if SMC- specific tamoxifen conditional KO of the IL1R1 receptor, after establishment of advanced atherosclerosis by 16- 18 weeks of WD feeding, results in loss of SMC fibrous cap coverage and other detrimental changes consistent with plaque destabilization. Finally, we will determine if IL1β dependent phenotypic changes of SMC observed in our mouse studies occur in human lesions and if these changes are predictive of plaque rupture or erosion. Aim 2 will define critical variables and mechanisms that influence the effects of IL1β neutralization on late stage lesion pathogenesis including those that may help to reconcile our findings with the recent positive outcomes of the CANTOS Clinical Trial. This will include testing the hypotheses that the response to anti-IL1β therapy is highly dependent on whether there is persistent hyperlipidemia/unresolved inflammation, and/or concurrent myocardial infarction/heart failure. Taken together, the proposed studies will provide key insights regarding fundamental mechanisms that regulate late stage lesion pathogenesis, and may contribute to development of improved therapies for treating patients with advanced atherosclerosis.

动脉粥样硬化是由于不稳定的动脉粥样硬化斑块破裂或侵蚀引起的，是导致的主要原因 全球死亡。但是，调节晚期动脉粥样硬化病变稳定性的机制仍然存在 理解不佳。教条是：1）包含大坏死核，纤维帽和大的斑块 相对于ACTA2+细胞的CD68+细胞数量[假定为巨噬细胞（MO）和平滑肌细胞 （SMC）分别更容易破裂； 2）SMC扮演有益的角色，因为它们是主要的 电池类型，负责形成富含基质的受保护纤维帽。但是，我们的实验室最近的研究 涉及干细胞多能基因的简单SMC谱系跟踪和SMC特异性敲除（KO） OCT4或KLF4，提供令人信服的证据挑战此教条，包括表明SMC可以具有重大 对晚期病变发病机理的有益或有害作用，具体取决于其表型的性质 过渡。因此，我们感觉到识别促进有益（动脉保护性）SMC表型的机制 过渡，并假设用抗IL1β抗体（AB）治疗全局抑制注射 会引起这种变化。但是，与期望完全对比，处理我们的SMC谱系追踪 ApoE - / - 抗IL1βAB在西方饮食18-26周之间导致多种有害变化 包括纤维盖厚度和胶原蛋白含量的明显减少，纤维帽SMC的快速损失和 替换为MOS，并向外损害重塑。该提议中的研究将检验以下假设 SMC中的IL1β信号在晚期病变发病机理中起着至关重要的作用 形成和维护受保护的纤维帽所需的。 AIM 1将确定是否持续IL1R1 维护SMC丰富的纤维帽需要SMC中的信号传导。研究将包括确定 每个IL1R1配体IL1β和IL1α以及IL1RA的贡献。我们还将确定是否SMC- 特异性的他莫昔芬的条件KO IL1R1受体，通过16-建立晚期动脉粥样硬化后 WD进食18周，导致SMC纤维盖覆盖范围损失和其他有害变化一致 斑块不稳定。最后，我们将确定观察到的SMC的IL1β依赖性表型变化是否依赖 在我们的小鼠研究中，发生在人体病变中，如果这些变化可以预测斑块破裂或侵蚀。 AIM 2将定义影响IL1β神经化对后期影响的临界变量和机制 病变发病机理，包括可能有助于调和我们发现与最近的正面结果的发病机理 Cantos临床试验。这将包括测试对抗IL1β治疗的反应的假设是 高度依赖是否存在持续性高脂血症/未解决的感染和/或并发 心肌梗塞/心力衰竭。综上所述，拟议的研究将提供有关有关的关键见解 调节晚期病变发病机理的基本机制，并可能有助于发展 改善了治疗晚期动脉粥样硬化患者的治疗方法。