Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (M.A.K., X.G., L.V., B.H., R.S., T.W., X.F., D.G.T., J.C.K., S.P.K., S.R.H., A.S.).
Thomas Jefferson University, Philadelphia, PA (K.R.).
Circulation. 2020 Aug 25;142(8):758-775. doi: 10.1161/CIRCULATIONAHA.119.044340. Epub 2020 Jun 3.
Cardiac rupture is a major lethal complication of acute myocardial infarction (MI). Despite significant advances in reperfusion strategies, mortality from cardiac rupture remains high. Studies suggest that cardiac rupture can be accelerated by thrombolytic therapy, but the relevance of this risk factor remains controversial.
We analyzed protease-activated receptor 4 (Par4) expression in mouse hearts with MI and investigated the effects of Par4 deletion on cardiac remodeling and function after MI by echocardiography, quantitative immunohistochemistry, and flow cytometry.
Par4 mRNA and protein levels were increased in mouse hearts after MI and in isolated cardiomyocytes in response to hypertrophic and inflammatory stimuli. Par4-deficient mice showed less myocyte apoptosis, reduced infarct size, and improved functional recovery after acute MI relative to wild-type (WT). Conversely, Par4 mice showed impaired cardiac function, greater rates of myocardial rupture, and increased mortality after chronic MI relative to WT. Pathological evaluation of hearts from Par4 mice demonstrated a greater infarct expansion, increased cardiac hemorrhage, and delayed neutrophil accumulation, which resulted in impaired post-MI healing compared with WT. Par4 deficiency also attenuated neutrophil apoptosis in vitro and after MI in vivo and impaired inflammation resolution in infarcted myocardium. Transfer of Par4 neutrophils, but not of Par4 platelets, in WT recipient mice delayed inflammation resolution, increased cardiac hemorrhage, and enhanced cardiac dysfunction. In parallel, adoptive transfer of WT neutrophils into Par4 mice restored inflammation resolution, reduced cardiac rupture incidence, and improved cardiac function after MI.
These findings reveal essential roles of Par4 in neutrophil apoptosis and inflammation resolution during myocardial healing and point to Par4 inhibition as a potential therapy that should be limited to the acute phases of ischemic insult and avoided for long-term treatment after MI.
心脏破裂是急性心肌梗死（MI）的主要致死性并发症。尽管再灌注策略有了显著进展，但心脏破裂导致的死亡率仍然很高。研究表明，溶栓治疗可能会加速心脏破裂，但这种风险因素的相关性仍存在争议。
我们分析了 MI 小鼠心脏中蛋白酶激活受体 4（Par4）的表达，并通过超声心动图、定量免疫组织化学和流式细胞术研究了 Par4 缺失对 MI 后心脏重构和功能的影响。
MI 后小鼠心脏和对肥大和炎症刺激的分离心肌细胞中 Par4 mRNA 和蛋白水平增加。与野生型（WT）相比，Par4 缺陷型小鼠的心肌细胞凋亡减少，梗死面积减小，急性 MI 后功能恢复改善。相反，慢性 MI 后 Par4 小鼠的心脏功能受损，心肌破裂发生率更高，死亡率增加。与 WT 相比，Par4 小鼠的心脏病理评估显示梗死扩张更大，心脏出血增加，中性粒细胞积聚延迟，导致 MI 后愈合受损。Par4 缺乏还减弱了体外中性粒细胞凋亡和体内 MI 后中性粒细胞凋亡，并损害了梗死心肌中的炎症消退。WT 受体小鼠中性粒细胞中 Par4 的转移，但不是 Par4 血小板的转移，延迟了炎症消退，增加了心脏出血，并加重了心脏功能障碍。与此平行的是，WT 中性粒细胞在 Par4 小鼠中的过继转移恢复了炎症消退，降低了 MI 后心脏破裂的发生率，并改善了心脏功能。
这些发现揭示了 Par4 在心肌愈合过程中中性粒细胞凋亡和炎症消退中的重要作用，并指出 Par4 抑制可能是一种潜在的治疗方法，这种方法应仅限于缺血性损伤的急性阶段，并避免在 MI 后长期治疗。
