Blood Journal
Leading the way in experimental and clinical research in hematology

Intracellular cyclophilin A is an important Ca2+ regulator in platelets and critically involved in arterial thrombus formation

  1. Margitta Elvers1,
  2. Annika Herrmann1,
  3. Peter Seizer1,
  4. Patrick Münzer2,
  5. Sandra Beck1,
  6. Tanja Schönberger1,
  7. Oliver Borst1,2,
  8. Francisco Javier Martin-Romero3,
  9. Florian Lang2,
  10. Andreas E. May1, and
  11. Meinrad Gawaz1
  1. 1Medizinische Klinik III, Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany;
  2. 2Department of Physiology, Eberhard Karls University, Tübingen, Germany; and
  3. 3Department of Biochemistry and Molecular Biology, College of Life Sciences, University of Extremadura, Badajoz, Spain

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 Ca2+ activity ([Ca2+]i). Activation-dependent depletion of intracellular Ca2+ stores triggers Ca2+ entry from the extracellular space. Stromal interaction molecule 1 (STIM1) has been identified as a Ca2+ sensor that regulates store-operated Ca2+ entry through activation of the pore-forming subunit Orai1, the major store-operated Ca2+ entry channel in platelets. In the present study, we show for the first time that the chaperone protein cyclophilin A (CyPA) acts as a Ca2+ modulator in platelets. CyPA deficiency strongly blunted activation-induced Ca2+ mobilization from intracellular stores and Ca2+ influx from the extracellular compartment and thus impaired platelet activation substantially. Furthermore, the phosphorylation of the Ca2+ 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 Ca2+ regulator in platelets, a critical mechanism for arterial thrombosis.

  • Submitted December 13, 2011.
  • Accepted June 14, 2012.
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