Panlai Shi1, Lin Zhang1, Mingliang Zhang2, Wenlong Yang2, Kemin Wang2, Junfeng Zhang2, Kinya Otsu2, Gonghua Huang1, Xuemei Fan1, Junling Liu1. 1. From the Department of Biochemistry and Molecular Cell Biology (P.S., L.Z., K.W., X.F., J.L.), Department of Cardiology, Ninth People's Hospital (M.Z., W.Y., J.Z.), and Shanghai Institute of Immunology (G.H.), Shanghai Jiao Tong University School of Medicine, China; and Cardiovascular Division, King's College London British Heart Foundation Centre of Research Excellence, United Kingdom (K.O.). liujl@shsmu.edu.cn fanxuemei1989@163.com gonghua.huang@shsmu.edu.cn. 2. From the Department of Biochemistry and Molecular Cell Biology (P.S., L.Z., K.W., X.F., J.L.), Department of Cardiology, Ninth People's Hospital (M.Z., W.Y., J.Z.), and Shanghai Institute of Immunology (G.H.), Shanghai Jiao Tong University School of Medicine, China; and Cardiovascular Division, King's College London British Heart Foundation Centre of Research Excellence, United Kingdom (K.O.).
Abstract
OBJECTIVE: MAPKs (mitogen-activated protein kinases), especially p38, play detrimental roles in cardiac diseases and cardiac remodeling post-myocardial infarction. However, the activation and function of MAPKs in coronary thrombosis in vivo and its relationship with clinical outcomes remain poorly understood. APPROACH AND RESULTS: Here, we showed that p38α was the major isoform expressed in human and mouse platelets. Platelet-specific p38α-deficient mice presented impaired thrombosis and hemostasis but had improved cardiac function, reduced infarct size, decreased inflammatory response, and microthrombus in a left anterior descending artery ligation model. Signaling analysis revealed that p38 activation was one of the earliest events in platelets after treatment with receptor agonists or reactive oxygen species. p38α/MAPK-activated protein kinase 2/heat shock protein 27 and p38α/cytosolic phospholipases A2 were the major pathways regulating receptor-mediated or hydrogen peroxide-induced platelet activation in an ischemic environment. Moreover, the distinct roles of ERK1/2 (extracellular signal-regulated kinase) in receptor- or reactive oxygen species-induced p38-mediated platelet activation reflected the complicated synergistic relationships among MAPKs. Analysis of clinical samples revealed that MAPKs were highly phosphorylated in platelets from preoperative patients with ST-segment-elevation myocardial infarction, and increased phosphorylation of p38 was associated with no-reflow outcomes. CONCLUSIONS: We conclude that p38α serves as a critical regulator of platelet activation and potential indicator of highly thrombotic lesions and no-reflow, and inhibition of platelet p38α may improve clinical outcomes in subjects with ST-segment-elevation myocardial infarction.
OBJECTIVE: MAPKs (mitogen-activated protein kinases), especially p38, play detrimental roles in cardiac diseases and cardiac remodeling post-myocardial infarction. However, the activation and function of MAPKs in coronary thrombosis in vivo and its relationship with clinical outcomes remain poorly understood. APPROACH AND RESULTS: Here, we showed that p38α was the major isoform expressed in human and mouse platelets. Platelet-specific p38α-deficient mice presented impaired thrombosis and hemostasis but had improved cardiac function, reduced infarct size, decreased inflammatory response, and microthrombus in a left anterior descending artery ligation model. Signaling analysis revealed that p38 activation was one of the earliest events in platelets after treatment with receptor agonists or reactive oxygen species. p38α/MAPK-activated protein kinase 2/heat shock protein 27 and p38α/cytosolic phospholipases A2 were the major pathways regulating receptor-mediated or hydrogen peroxide-induced platelet activation in an ischemic environment. Moreover, the distinct roles of ERK1/2 (extracellular signal-regulated kinase) in receptor- or reactive oxygen species-induced p38-mediated platelet activation reflected the complicated synergistic relationships among MAPKs. Analysis of clinical samples revealed that MAPKs were highly phosphorylated in platelets from preoperative patients with ST-segment-elevation myocardial infarction, and increased phosphorylation of p38 was associated with no-reflow outcomes. CONCLUSIONS: We conclude that p38α serves as a critical regulator of platelet activation and potential indicator of highly thrombotic lesions and no-reflow, and inhibition of platelet p38α may improve clinical outcomes in subjects with ST-segment-elevation myocardial infarction.
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