title: Cyclophilin A is an important mediator of platelet function by regulating integrin αIIbβ3 bidirectional signalling.
abstract: Cyclophilin A (CyPA) is an important mediator in cardiovascular diseases. It possesses peptidyl-prolyl cis-trans isomerase activity (PPIase) and chaperone functions, which regulate protein folding, intracellular trafficking and reactive oxygen species (ROS) production. Platelet glycoprotein receptor αIIbβ3 integrin activation is the common pathway for platelet activation. It was our objective to understand the mechanism by which CyPA-regulates αIIbβ3 activation in platelets. Mice deficient for CyPA (CyPA-/-) had prolonged tail bleeding time compared to wild-type (WT) controls despite equivalent platelet numbers. In vitro studies revealed that CyPA-/- platelets exhibited dramatically decreased thrombin-induced platelet aggregation. In vivo, formation of occlusive thrombi following FeCl3 injury was also significantly impaired in CyPA-/- mice compared with WT-controls. Furthermore, CyPA deficiency inhibited flow-induced thrombus formation in vitro. Flow cytometry demonstrated that thrombin-induced ROS production and αIIbβ3 activation were reduced in CyPA-/- platelets. Coimmunoprecipitation studies showed ROS-dependent increased association of CyPA and αIIbβ3. This association was dependent upon the PPIase activity of CyPA. Significantly, fibrinogen-platelet binding, platelet spreading and cytoskeleton reorganisation were also altered in CyPA-/- platelets. Moreover, CyPA deficiency prevented thrombin-induced αIIbβ3 and cytoskeleton association. In conclusion, CyPA is an important mediator in platelet function by regulation of αIIbβ3 bidirectionalsignalling through increased ROS production and facilitating interaction between αIIbβ3 and the cell cytoskeleton.
authors.forename: Lian
authors.initials: L
authors.lastname: Wang
authors.forename: Nwe Nwe
authors.initials: NN
authors.lastname: Soe
authors.forename: Mark
authors.initials: M
authors.lastname: Sowden
authors.forename: Yingqian
authors.initials: Y
authors.lastname: Xu
authors.forename: Kristina
authors.initials: K
authors.lastname: Modjeski
authors.forename: Padmamalini
authors.initials: P
authors.lastname: Baskaran
authors.forename: Yeonghwan
authors.initials: Y
authors.lastname: Kim
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Smolock
authors.forename: Craig N
authors.initials: CN
authors.lastname: Morrell
authors.affiliation: Bradford C. Berk, MD, PhD, Aab Cardiovascular Research Institute, University of Rochester, Box CVRI, 601 Elmwood Avenue, Rochester, NY 14642, USA, Tel.: +1 585 275 3407, Fax: +1 585 273 1059, E-mail: bradford_berk@urmc.rochester.edu.
authors.forename: Bradford C
authors.initials: BC
authors.lastname: Berk
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D002448:Cell Adhesion / Q000235:genetics; D002478:Cells, Cultured; D002712:Chlorides / Q000008:administration & dosage; D021984:Cyclophilin A / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000235:genetics; D005290:Ferric Compounds / Q000008:administration & dosage; D005340:Fibrinogen / Q000378:metabolism; D006470:Hemorrhage / Q000235:genetics; D008638:Mesenteric Arteries / Q000187:drug effects / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010974:Platelet Aggregation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood* / Q000139:chemically induced
chemical_list: D002712:Chlorides; D005290:Ferric Compounds; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D017382:Reactive Oxygen Species; D005340:Fibrinogen; D013917:Thrombin; D021984:Cyclophilin A; C024555:ferric chloride
keywords: Platelets; cell cytoskeleton; cyclophilin A; integrin αIIbβ3; thrombin