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J. Exp. Med. 205 (7): 1583-1591

Copyright © 2008 by the Rockefeller University Press.

BRIEF DEFINITIVE REPORT

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

David Varga-Szabo1, Attila Braun1, Christoph Kleinschnitz2, Markus Bender1, Irina Pleines1, Mirko Pham3,5, Thomas Renné4, Guido Stoll2, , and Bernhard Nieswandt1,4

1 Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, 2 Department of Neurology, 3 Department of Neuroradiology, and 4 Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, 97078 Würzburg, Germany
5 Department of Neuroradiology, University of Heidelberg, 69120 Heidelberg, Germany

CORRESPONDENCE Bernhard Nieswandt: bernhard.nieswandt{at}virchow.uni-wuerzburg.de

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.

D. Varga-Szabo and A. Braun contributed equally to this paper.

© 2008 Varga-Szabo et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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