title: P2Y12Promotes Migration of Vascular Smooth Muscle Cells Through Cofilin Dephosphorylation During Atherogenesis.
abstract: OBJECTIVE
  P2Y12is a well-recognized receptor expressed on platelets and the target of thienopyridine-type antiplatelet drugs. However, recent evidence suggests that P2Y12expressed in vessel wall plays a role in atherogenesis, but the mechanisms remain elusive. In this study, we examined the molecular mechanisms of how vessel wall P2Y12mediates vascular smooth muscle cells (VSMCs) migration and promotes the progression of atherosclerosis.
  
  
  RESULTS
  Using a high-fat diet-fed apolipoprotein E-deficient mice model, we found that the expression of P2Y12in VSMCs increased in a time-dependent manner and had a linear relationship with the plaque area. Moreover, administration of P2Y12receptor antagonist for 12 weeks caused significant reduction in atheroma and decreased the abundance of VSMCs in plaque. In cultured VSMCs, we found that activation of P2Y12receptor inhibited cAMP/protein kinase A signaling pathway, which induced cofilin dephosphorylation and filamentous actin disassembly, thereby enhancing VSMCs motility and migration. In addition, the number of P2Y12-positive VSMCs was decreased in the carotid artery plaque from patients receiving clopidogrel.
  
  
  CONCLUSIONS
  Vessel wall P2Y12receptor, which promotes VSMCs migration through cofilin dephosphorylation, plays a critical role in the development of atherosclerotic lesion and may be used as a therapeutic target for atherosclerosis.
authors.affiliation: From the Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Niu
authors.affiliation: From the Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Shu-Lan
authors.initials: SL
authors.lastname: Pi
authors.affiliation: From the Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Suraj
authors.initials: S
authors.lastname: Baral
authors.affiliation: From the Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yuan-Peng
authors.initials: YP
authors.lastname: Xia
authors.affiliation: From the Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Quan-Wei
authors.initials: QW
authors.lastname: He
authors.affiliation: From the Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Li
authors.affiliation: From the Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Hui-Juan
authors.initials: HJ
authors.lastname: Jin
authors.affiliation: From the Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.affiliation: From the Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Meng-Die
authors.initials: MD
authors.lastname: Wang
authors.affiliation: From the Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. hubo@mail.hust.edu.cn maoling13096@163.com.
authors.forename: Ling
authors.initials: L
authors.lastname: Mao
authors.affiliation: From the Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. hubo@mail.hust.edu.cn maoling13096@163.com.
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D000077144:Clopidogrel; D051340:Cofilin 2 / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation; D058226:Plaque, Atherosclerotic; D058921:Purinergic P2Y Receptor Antagonists / Q000627:therapeutic use; D034622:RNA Interference; D058925:Receptors, Purinergic P2Y12 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D013997:Time Factors; D014162:Transfection
chemical_list: D001057:Apolipoproteins E; C495816:Cfl2 protein, mouse; D051340:Cofilin 2; C548576:P2RY12 protein, human; C548577:P2ry12 protein, mouse; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D013988:Ticlopidine
keywords: actin cytoskeleton; atherosclerosis; signal transduction; smooth muscle cell migration