IL-1 Beta Signaling Promotes Atherosclerotic Calcification and Cardiovascular Risk

钙化性动脉粥样硬化引起的冠状动脉疾病是老年人发病率和死亡率的主要原因。 世界动脉粥样硬化斑块的钙成分对心血管疾病有预测价值 事件炎症可能是血管钙化的关键介质，但免疫信号机制， 这一过程的推进，人们了解得最少。最近，炎性细胞因子IL-1β被鉴定为 ApoE-/-背景小鼠的钙化动脉粥样硬化斑块增加。此外，委员会认为， 来自具有进行性钙化的小鼠的斑块和血清显示IL-1β表达增加。 用IL-1受体拮抗剂治疗可抑制动脉粥样硬化钙化。IL-1β的表达是一个关键因素， 驱动血管平滑肌细胞钙沉积的能力，促进成骨细胞的表达， 转录因子RUNX 2、SOX 9、OSX和MSX 2。骨髓移植证实， 斑块的钙化可归因于造血区室。几个关键问题仍然存在：1） 巨噬细胞是动脉粥样硬化钙化过程中斑块IL-1β的关键细胞来源; 2）使血管平滑 肌细胞呈现炎性表型以促进斑块IL-1β表达; 3） 斑块巨噬细胞和血管平滑肌细胞上的IL-1受体信号传导; 4）IL-1如何 受体信号传导导致成骨基因程序;和5）IL-1β能否作为进行性骨坏死的生物标志物 冠状动脉疾病患者的钙化。初步数据表明，巨噬细胞出现 与斑块中IL-1β的表达相关，因此，IL-1β通过其受体的信号传导可能起作用。 自分泌正反馈作用促进巨噬细胞进一步表达IL-1β。血管平滑肌 相比之下，肌肉细胞似乎通过激活成骨基因对IL-1β信号传导起反应作用， 程序.然而，IL-1受体的整体缺失显示了关于是否 非特异性抑制IL-1β信号传导可以防止斑块易损性，这表明进一步的研究 描述细胞特异性的贡献在这一途径是必需的。假设巨噬细胞表达 IL-1β在动脉粥样硬化斑块中的表达及随后的血管细胞IL-1受体信号转导导致炎症反应， 动脉粥样硬化钙化导致斑块破裂的风险增加。目的1：明确巨噬细胞IL-1β的定义 表达是炎症性动脉粥样硬化钙化的关键。目标2将确定各自的作用 巨噬细胞和平滑肌细胞IL-1受体信号在炎症性动脉粥样硬化钙化和 成骨转录因子表达。目的3将验证血清IL-1β作为一种重要的生物标志物， 进行性冠状动脉钙化。这表明巨噬细胞IL-1β信号传导轴是一个重要的细胞因子。 炎症性动脉粥样硬化钙化的中枢机制在临床前和转化研究中的应用 开发一种新的治疗策略的方式，旨在治疗冠状动脉疾病的风险，如抗IL- 1β疗法已经开发出来，并正在积极研究中。

Coronary artery disease from calcific atherosclerosis is the leading cause of morbidity and mortality in the world. The calcium composition of atherosclerotic plaque has predictive value in terms of cardiovascular events. Inflammation is likely a key mediator of vascular calcification, but immune signaling mechanisms that promote this process are minimally understood. Recently, the inflammatory cytokine, IL-1β, was identified to be increased in calcifying atherosclerotic aortas from ApoE-/- background mice fed a high fat diet. Moreover, plaque and serum from mice with progressive calcification demonstrated increased expression of IL-1β. Treatment with the IL-1 receptor antagonist inhibited atherosclerotic calcification. IL-1β expression was a key driver of vascular smooth muscle cell calcium deposition by its ability to promote expression of the osteogenic transcription factors, RUNX2, SOX9, OSX and MSX2. Bone marrow transplantation confirmed that progressive calcification of plaque is attributable to the hematopoietic compartment. Several key questions remain: 1) are macrophages the key cellular source of plaque IL-1β during atherosclerotic calcification; 2) do vascular smooth muscle cells take on an inflammatory phenotype to promote plaque IL-1β expression; 3) what are the effects of IL-1 receptor signaling on both plaque macrophages and vascular smooth muscle cells; 4) how does IL-1 receptor signaling lead to an osteogenic gene program; and 5) can IL-1β serve as a biomarker of progressive calcification in patients with coronary artery disease. Preliminary data demonstrated that macrophages appear associated with expression of IL-1β in plaque, and consequently, IL-1β signaling through its receptor may play an autocrine positive feedback role in promoting further IL-1β expression by macrophages. Vascular smooth muscle cells, in contrast, appear to play a responsive role to IL-1β signaling by activating an osteogenic gene program. However, global deletion of the IL-1 receptor demonstrated conflicting data about whether nonspecific inhibition of IL-1β signaling can protect against plaque vulnerability, indicating further study to delineate cell-specific contributions in this pathway is required. The hypothesis is that macrophage expression of IL-1β in atherosclerotic plaque and consequent vascular cell IL-1 receptor signaling lead to inflammatory atherosclerotic calcification resulting in increased risk of plaque rupture. Aim 1 will define macrophage IL-1β expression as the critical to inflammatory atherosclerotic calcification. Aim 2 will determine the respective roles of macrophage and smooth muscle cell IL-1 receptor signaling in inflammatory atherosclerotic calcification and osteogenic transcription factor expression. Aim 3 will validate serum IL-1β as a critical biomarker of progressive coronary artery calcification in patients. Confirming that a macrophage IL-1β signaling axis is a central mechanism in inflammatory atherosclerotic calcification in preclinical and translational studies paves the way for developing a novel therapeutic strategy aimed at treating risk in coronary artery disease, as anti-IL- 1β therapies have been developed and are actively under investigation.