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The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction

Authors :
Christoph Kleinschnitz
Guido Stoll
David Varga-Szabo
Markus Bender
Irina Pleines
Bernhard Nieswandt
Mirko Pham
Attila Braun
Thomas Renné
Source :
The Journal of Experimental Medicine
Publication Year :
2008

Abstract

Platelet activation and aggregation are essential to limit posttraumatic blood loss at sites of vascular injury but also contributes to arterial thrombosis, leading to myocardial infarction and stroke. Agonist-induced elevation of [Ca2+]i is a central step in platelet activation, but the underlying mechanisms are not fully understood. A major pathway for Ca2+ entry in nonexcitable cells involves receptor-mediated release of intracellular Ca2+ stores, followed by activation of store-operated calcium (SOC) channels in the plasma membrane. Stromal interaction molecule 1 (STIM1) has been identified as the Ca2+ sensor in the endoplasmic reticulum (ER) that activates Ca2+ release–activated channels in T cells, but its role in mammalian physiology is unknown. Platelets express high levels of STIM1, but its exact function has been elusive, because these cells lack a normal ER and Ca2+ is stored in a tubular system referred to as the sarcoplasmatic reticulum. We report that mice lacking STIM1 display early postnatal lethality and growth retardation. STIM1-deficient platelets have a marked defect in agonist-induced Ca2+ responses, and impaired activation and thrombus formation under flow in vitro. Importantly, mice with STIM1-deficient platelets are significantly protected from arterial thrombosis and ischemic brain infarction but have only a mild bleeding time prolongation. These results establish STIM1 as an important mediator in the pathogenesis of ischemic cardio- and cerebrovascular events.

Details

ISSN :
15409538
Volume :
205
Issue :
7
Database :
OpenAIRE
Journal :
The Journal of experimental medicine
Accession number :
edsair.doi.dedup.....378adf03eafcb9f351df3afd3beff1d9