期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1864, 期 9, 页码 2901-2912出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2018.05.025
关键词
CCL2; CCR2; Platelet activation; Arterial thrombosis; PKC alpha; P38MAPK
资金
- National Young Science Foundation of China [81500282]
- Key Project of National 13th Five-Year Research Program of China [2016YFC1301300]
- National Natural Science Foundation of China [81670340, 81570767]
Background: Studies indicate that chemokine CC-motif ligand 2 (CCL2) is involved in inflammation and atherosclerosis. However, the roles and mechanisms of CCL2 on platelet function and arterial thrombosis are unknown. Methods: The expressions of CCL2 or CCR2 in the plasma, platelets and coronary thrombus of ST-elevated myocardial infarction (STEMI) patients were examined by ELISA, Western blot, immunohistochemistry and immunofluorescence. The roles of CCL2 on platelet aggregation, activation and secretion were examined by light transmission aggregometry, flow cytometry and ELISA. Results: The expressions of CCL2 or CCR2 in the plasma or platelets of STEMI patients with platelet high response were higher than those with platelet normal response; In vitro, exogenous recombinant human CCL2 markedly increased platelet aggregation, activation and granule secretion, which were abolished by CCL2 neutralizing antibody or CCR2 inhibiter. CCL2 increased the phosphorylation levels of PKC alpha (Thr638), P38MAPK (Thr180/Tyr182) and HSP27 (S78/S82) in human platelets, which were abrogated by PKC alpha inhibitor (RO 318220) or P38MAPK inhibitor (SB 203580). RO 318220 or SB 203580 diminished CCL2-induced platelet function. In CCL2(-/-) mice, platelet aggregation and secretion were attenuated; the phosphorylation of PKC alpha, P38MAPK and HSP27 were decreased. In a carotid arterial thrombus mouse model, CCL2(-/-) mice displayed a significantly extended carotid artery occlusion time compared with wild type. Conclusions: CCL2 played important roles in regulating platelet function and arterial thrombosis through the PKC alpha-P38MAPK-HSP27 pathway, which might provide theoretical basis for searching new antiplatelet drugs and the treatment for cardiovascular diseases.
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