title: Intracellular cyclophilin A is an important Ca(2+) regulator in platelets and critically involved in arterial thrombus formation.
abstract: Platelet adhesion and aggregation play a critical role in primary hemostasis. Uncontrolled platelet activation leads to pathologic thrombus formation and organ failure. The decisive central step for different processes of platelet activation is the increase in cytosolic Ca(2+) activity ([Ca(2+)](i)). Activation-dependent depletion of intracellular Ca(2+) stores triggers Ca(2+) entry from the extracellular space. Stromal interaction molecule 1 (STIM1) has been identified as a Ca(2+) sensor that regulates store-operated Ca(2+) entry through activation of the pore-forming subunit Orai1, the major store-operated Ca(2+) entry channel in platelets. In the present study, we show for the first time that the chaperone protein cyclophilin A (CyPA) acts as a Ca(2+) modulator in platelets. CyPA deficiency strongly blunted activation-induced Ca(2+) mobilization from intracellular stores and Ca(2+) influx from the extracellular compartment and thus impaired platelet activation substantially. Furthermore, the phosphorylation of the Ca(2+) sensor STIM1 was abrogated upon CyPA deficiency, as shown by immunoprecipitation studies. In a mouse model of arterial thrombosis, CyPA-deficient mice were protected against arterial thrombosis, whereas bleeding time was not affected. The results of the present study identified CyPA as an important Ca(2+) regulator in platelets, a critical mechanism for arterial thrombosis.
authors: Medizinische Klinik III, Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany. margitta.elvers@med.uni-tuebingen.de
authors: Margitta
authors: M
authors: Elvers
authors: Annika
authors: A
authors: Herrmann
authors: Peter
authors: P
authors: Seizer
authors: Patrick
authors: P
authors: Münzer
authors: Sandra
authors: S
authors: Beck
authors: Tanja
authors: T
authors: Schönberger
authors: Oliver
authors: O
authors: Borst
authors: Francisco Javier
authors: FJ
authors: Martin-Romero
authors: Florian
authors: F
authors: Lang
authors: Andreas E
authors: AE
authors: May
authors: Meinrad
authors: M
authors: Gawaz
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics; D015550:Cell Degranulation / Q000235:genetics / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D021984:Cyclophilin A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D039661:Integrin beta3 / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D058729:Peripheral Arterial Disease / Q000235:genetics / Q000378:metabolism; D015539:Platelet Activation / Q000235:genetics; D013927:Thrombosis / Q000235:genetics* / Q000378:metabolism
chemical_list: D039661:Integrin beta3; D021984:Cyclophilin A; D002118:Calcium