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

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 -