title: Platelet PI3Kγ Contributes to Carotid Intima-Media Thickening under Severely Reduced Flow Conditions.
abstract: Studies have begun to focus on the emerging function of platelets as immune and inflammatory cells that initiate and accelerate vascular inflammation. Phosphoinositide 3-kinase gamma (PI3Kγ) is critically involved in a number of inflammatory and autoimmune diseases. This study aims to investigate the contribution of platelet PI3Kγ to vascular remodeling under flow severely reduced conditions. Mouse partial left carotid artery ligation with adoptive transfer of activated, washed wild-type or PI3Kγ-/- platelets was used as the model. Intima-media area, leukocyte recruitment, and proinflammatory mediator expression were assessed. In vitro PI3Kγ-/- platelets were used to verify the effect of PI3Kγ on platelet activation, interaction with leukocytes, and endothelial cells. Mice injected with activated platelets showed a significant increase in intima-media thickening, recruitment of neutrophils (at 3 d) and macrophages (at 21 d), and intercellular adhesion molecule-1, vascular cell adhesion molecule-1, tumor necrosis factor alpha, and interleukin-6 expression (at 3 d) in the flow-reduced area. These effects were abrogated by platelet PI3Kγ deficiency. Circulating platelet-leukocyte aggregates were reduced in PI3Kγ-/- mice after partial ligation. In vivo data confirmed that PI3Kγ mediated Adenine di-Phosphate -induced platelet activation through the Akt and p38 MAP kinase signaling pathways. Moreover, platelet PI3Kγ deficiency reduced platelet-leukocyte aggregation and platelet-endothelial cell (EC) interaction. These findings indicate that platelet PI3Kγ contributes to platelet-mediated vascular inflammation and carotid intima-media thickening after flow severely reduced. Platelet PI3Kγ may be a new target in the treatment of vascular diseases.
authors.affiliation: Department of Cardiolog, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, 212001, P. R. China; Department of Neurosurgery, LSU Health Science Center, Shreveport, LA, 71103, United States of America.
authors.forename: Cuiping
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, LSU Health Science Center, Shreveport, LA, 71103, United States of America.
authors.forename: Rong
authors.initials: R
authors.lastname: Jin
authors.affiliation: Department of Neurosurgery, LSU Health Science Center, Shreveport, LA, 71103, United States of America.
authors.forename: Anil
authors.initials: A
authors.lastname: Nanda
authors.affiliation: Department of Cardiolog, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, 212001, P. R. China.
authors.forename: Jinchuan
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Neurosurgery, LSU Health Science Center, Shreveport, LA, 71103, United States of America.
authors.forename: Guohong
authors.initials: G
authors.lastname: Li
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002340:Carotid Artery Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D002448:Cell Adhesion; D002450:Cell Communication; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D015870:Gene Expression; D006439:Hemodynamics; D018836:Inflammation Mediators / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D015539:Platelet Activation / Q000187:drug effects / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D000244:Adenosine Diphosphate; D058544:Class Ib Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases