The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction
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The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction. / Varga-Szabo, David; Braun, Attila; Kleinschnitz, Christoph; Bender, Markus; Pleines, Irina; Pham, Mirko; Renné, Thomas; Stoll, Guido; Nieswandt, Bernhard.
In: J EXP MED, Vol. 205, No. 7, 07.07.2008, p. 1583-91.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction
AU - Varga-Szabo, David
AU - Braun, Attila
AU - Kleinschnitz, Christoph
AU - Bender, Markus
AU - Pleines, Irina
AU - Pham, Mirko
AU - Renné, Thomas
AU - Stoll, Guido
AU - Nieswandt, Bernhard
PY - 2008/7/7
Y1 - 2008/7/7
N2 - 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.
AB - 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.
KW - Animals
KW - Bleeding Time
KW - Brain Infarction
KW - Calcium
KW - Calcium Channels
KW - Growth Disorders
KW - Hemorrhage
KW - Membrane Glycoproteins
KW - Mice
KW - Mice, Knockout
KW - Platelet Aggregation
KW - Sarcoplasmic Reticulum
KW - T-Lymphocytes
KW - Thrombosis
U2 - 10.1084/jem.20080302
DO - 10.1084/jem.20080302
M3 - SCORING: Journal article
C2 - 18559454
VL - 205
SP - 1583
EP - 1591
JO - J EXP MED
JF - J EXP MED
SN - 0022-1007
IS - 7
ER -