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: Margitta Elvers, Annika Herrmann, Peter Seizer, Patrick Münzer, Sandra Beck, Tanja Schönberger, Oliver Borst, Francisco Javier Martin-Romero, Florian Lang, Andreas E May, Meinrad Gawaz
• Journal: Blood (Blood) Vol. 120 Issue 6 Pg. 1317-26 (Aug 09 2012) ISSN: 1528-0020 [Electronic] United States
• PMID: 22740452 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Integrin beta3
• Cyclophilin A
• Calcium

Topics

• Animals
• Blood Platelets (metabolism)
• CHO Cells
• Calcium (metabolism)
• Calcium Signaling (genetics)
• Cell Degranulation (genetics, physiology)
• Cricetinae
• Cricetulus
• Cyclophilin A (genetics, metabolism, physiology)
• Integrin beta3 (metabolism)
• Intracellular Space (metabolism)
• Mice
• Mice, Knockout
• Models, Biological
• Peripheral Arterial Disease (genetics, metabolism)
• Platelet Activation (genetics)
• Thrombosis (genetics, metabolism)