The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction.
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 [Ca(2+)](i) is a central step in platelet activation, but the underlying mechanisms are not fully understood. A major pathway for Ca(2+) entry in nonexcitable cells involves receptor-mediated release of intracellular Ca(2+) stores, followed by activation of store-operated calcium (SOC) channels in the plasma membrane. Stromal interaction molecule 1 (STIM1) has been identified as the Ca(2+) sensor in the endoplasmic reticulum (ER) that activates Ca(2+) 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 Ca(2+) 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 Ca(2+) 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.
Varga-Szabo
David
D
Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, 97078 Würzburg, Germany.
Braun
Attila
A
Kleinschnitz
Christoph
C
Bender
Markus
M
Pleines
Irina
I
Pham
Mirko
M
Renné
Thomas
T
Stoll
Guido
G
Nieswandt
Bernhard
B
D000818:Animals; D001760:Bleeding Time; D020520:Brain Infarction / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D006130:Growth Disorders / Q000235:genetics / Q000378:metabolism; D006470:Hemorrhage / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010974:Platelet Aggregation / Q000235:genetics; D012519:Sarcoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D000071737:Stromal Interaction Molecule 1; D013601:T-Lymphocytes / Q000378:metabolism; D013927:Thrombosis / Q000235:genetics / Q000378:metabolism*
D015220:Calcium Channels; D008562:Membrane Glycoproteins; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D002118:Calcium