Inflammasome activation promotes myocardial injury and associated atherosclerosis following myocardial IRI

心肌 IRI 后炎症小体激活促进心肌损伤和相关动脉粥样硬化

• 批准号: 426472339
• 负责人: Dr. Khurrum Shahzad
• 金额: --
• 依托单位: Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/426472339?language=en
• 关键词: Inflammasome; activation; promotes; myocardial; injury

We recently demonstrated that the cytoprotective coagulation protease activated protein C (aPC) protects from myocardial ischemia-reperfusion injury (IRI) by restricting Nlrp3 inflammasome activation, revealing a novel anti-inflammatory target of aPC. The protective effect of aPC in the heart was mimicked by 3K3A-aPC (a cyto-protective, non-anti-coagulant aPC mutant) or parmodulin-2 (a biased agonist mimicking aPC signaling via proteinase-activated receptor 1), but was lost in mice expressing a hyperactive NLRP3 variant. In addition, inflammasome activation and associated cell death (pyroptosis) preceded apoptosis in myocardial IRI. Inflammasome activation was apparent in both immune and non-immune cells (cardiomyocyte and cardiac fibroblast) in myocardial IRI. While providing novel insights, important questions remain open: 1) It is unknown whether the induction of apoptosis at later stages following IRI may prevent excessive inflammation, thus providing protection in IRI. 2) The mechanisms controlling inflammasome activation in myocardial IRI are not known. 3) The relative contribution of cardiac resident cells and immune cells to inflammasome activation in myocardial IRI remains unclear. 4) The potential role of the non-canonical inflammasome are unknown. 5) It is not known whether the inflammasome activation associated with myocardial IRI contributes to the accelerated atherosclerosis following myocardial IRI.Based on published and preliminary work we will study the following goals to address these questions: Goal 1: Defining the causal contribution of pyroptosis versus apoptosis in myocardial IRI and the cell-autonomous effects of inflammasome activation in cardiac resident cells.Goal 2: Deciphering the mechanism through which aPC regulates inflammasome activity in myocardial IRI and cardiac dysfunction.Goal 3: Characterizing the relevance of inflammasome activation for myocardial IRI-mediated accelerated atherosclerosis.Collectively, we expect that these studies will provide novel insights into the mechanism through which inflammasome activation in myocardial IRI contributes to myocardial damage and dysfunction and to an acceleration of atherosclerosis. The delineation of these mechanisms may identify new therapeutic targets (e.g. targeting a specific cell-type or only the canonical inflammasome activation pathway) to combat the consequences of myocardial IRI.

我们最近证明了细胞保护性凝固蛋白酶激活蛋白C（aPC）通过限制Nlrp 3炎性体激活来保护心肌免受缺血再灌注损伤（IRI），揭示了aPC的新的抗炎靶点。aPC在心脏中的保护作用由3 K3 A-aPC（细胞保护性非抗凝aPC突变体）或parmodulin-2（通过蛋白酶激活受体1模拟aPC信号传导的偏向激动剂）模拟，但在表达过度活跃的NLRP 3变体的小鼠中丧失。此外，在心肌IRI中，炎性小体激活和相关的细胞死亡（焦亡）先于细胞凋亡。心肌IRI中的免疫细胞和非免疫细胞（心肌细胞和心脏成纤维细胞）中的炎症体激活均明显。虽然提供了新的见解，但重要的问题仍然是开放的：1） 目前尚不清楚在IRI后的后期诱导细胞凋亡是否可以防止过度炎症，从而在IRI中提供保护。（二） 控制心肌IRI中炎性小体激活的机制尚不清楚。第三章 在心肌IRI中，心肌驻留细胞和免疫细胞对炎性小体激活的相对贡献尚不清楚。四、 非典型炎性小体的潜在作用尚不清楚。第五章） 目前尚不清楚与心肌IRI相关的炎性小体激活是否有助于心肌IRI后加速动脉粥样硬化。基于已发表的和初步的工作，我们将研究以下目标来解决这些问题：目标1：确定心肌IRI中细胞凋亡与细胞凋亡的因果关系，以及心脏驻留细胞中炎性小体激活的细胞自主效应。目标2：解读aPC调节心肌IRI和心功能不全中炎性小体活性的机制。目标3：表征炎性小体激活与心肌IRI介导的加速动脉粥样硬化的相关性。我们预计这些研究将为心肌IRI中炎性小体激活导致心肌损伤的机制提供新的见解，功能障碍和动脉粥样硬化的加速。这些机制的描述可以识别新的治疗靶点（例如，靶向特定细胞类型或仅靶向典型炎性小体激活途径），以对抗心肌IRI的后果。