Loss of Protease-Activated Receptor 4 Prevents Inflammation Resolution and Predisposes the Heart to Cardiac Rupture After Myocardial Infarction.
Loss of Protease-Activated Receptor 4 Prevents Inflammation Resolution and Predisposes the Heart to Cardiac Rupture After Myocardial Infarction.
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DOI：
10.1161/circulationaha.119.044340
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发表时间：
2020-08-25
期刊：
影响因子：
37.8
通讯作者：
Sabri, Abdelkarim
中科院分区：
文献类型：
--
作者：
Kolpakov, Mikhail A.;Guo, Xinji;Rafiq, Khadija;Vlasenko, Liudmila;Hooshdaran, Bahman;Seqqat, Rachid;Wang, Tao;Fan, Xiaoxuan;Tilley, Douglas G.;Kostyak, John C.;Kunapuli, Satya P.;Houser, Steven R.;Sabri, Abdelkarim
心脏破裂是急性心肌梗死（MI）的主要致死性并发症。尽管再灌注策略取得了重大进展，但心脏破裂的死亡率仍然很高。研究表明，溶栓治疗可加速心脏破裂，但该危险因素的相关性仍存在争议。我们分析了蛋白酶激活受体（Par）4在MI小鼠心脏中的表达，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Par 4缺失对MI后心脏重构和功能的影响。心肌梗死后小鼠心脏和分离的心肌细胞中的Par 4 mRNA和蛋白水平在肥大和炎症刺激下增加。相对于野生型（WT），Par 4缺陷型小鼠在急性MI后表现出更少的心肌细胞凋亡、更小的梗死面积和更好的功能恢复。相反，与WT相比，Par 4 −/−小鼠表现出心脏功能受损，心肌破裂率更高，慢性MI后死亡率增加。对Par 4 −/−小鼠心脏的病理学评价表明，与WT相比，梗死范围扩大，心脏出血增加，中性粒细胞蓄积延迟，导致MI后愈合受损。Par 4缺陷还在体外和体内MI后减弱中性粒细胞凋亡，并损害梗死心肌中的炎症消退。在WT受体小鼠中，Par 4 −/−中性粒细胞的转移，而不是Par 4 −/−血小板的转移，延迟了炎症消退，增加了心脏出血和增强了心功能障碍。同时，将WT中性粒细胞过继转移到Par 4 −/−小鼠中恢复了炎症消退，降低了心脏破裂发生率并改善了MI后的心脏功能。这些发现揭示了Par 4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Par 4抑制作为潜在的治疗方法，应限于缺血性损伤的急性期，并应避免MI后的慢性治疗。
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 (Par)4 expression in mouse hearts with MI and investigated the effects of Par4 deletion on cardiac remodeling and function post-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 to 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 post-MI. These findings reveal essential roles of Par4 in neutrophil apoptosis and inflammation resolution during myocardial healing and point to Par4 inhibition as potential therapy that should be limited to the acute phases of ischemic insult and to be avoided for chronic treatment post-MI.