Inflammasome activation promotes myocardial injury and associated atherosclerosis following myocardial IRI

我们最近证明了细胞保护性凝血蛋白酶激活蛋白C （aPC）通过限制Nlrp3炎性体的激活来保护心肌缺血再灌注损伤（IRI），揭示了aPC的一个新的抗炎靶点。aPC在心脏中的保护作用被3K3A-aPC（一种细胞保护、非抗凝aPC突变体）或parmodulin-2（一种通过蛋白酶激活受体1模拟aPC信号的偏向性激动剂）模仿，但在表达过度活跃的NLRP3变体的小鼠中失去了作用。此外，在心肌IRI中，炎症小体激活和相关的细胞死亡（焦亡）先于细胞凋亡。在心肌IRI中，免疫细胞和非免疫细胞（心肌细胞和心肌成纤维细胞）的炎性小体活化都很明显。虽然提供了新的见解，但重要的问题仍未解决：1)尚不清楚在IRI后后期诱导凋亡是否可以防止过度炎症，从而在IRI中提供保护。2)心肌IRI中控制炎性体激活的机制尚不清楚。3)心肌IRI中心肌常驻细胞和免疫细胞在炎性小体活化中的相对作用尚不清楚。4)非典型炎性体的潜在作用尚不清楚。5)与心肌IRI相关的炎性体激活是否有助于心肌IRI后动脉粥样硬化的加速，目前尚不清楚。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中焦亡与凋亡的因果关系，以及心脏驻留细胞中炎症小体活化的细胞自主效应。目标2：破译aPC调控心肌IRI和心功能障碍中炎性体活性的机制。目的3：表征炎症小体激活与心肌iri介导的加速动脉粥样硬化的相关性。总的来说，我们期望这些研究将为心肌IRI中炎症小体激活导致心肌损伤和功能障碍以及加速动脉粥样硬化的机制提供新的见解。这些机制的描述可能会确定新的治疗靶点（例如针对特定细胞类型或仅针对典型炎性体激活途径）来对抗心肌IRI的后果。

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.