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The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction
- 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.
- Subjects :
- inorganic chemicals
Brain Infarction
medicine.medical_specialty
Bleeding Time
Platelet Aggregation
T-Lymphocytes
Immunology
Infarction
Hemorrhage
Mice
Internal medicine
medicine
Immunology and Allergy
Animals
Platelet
Platelet activation
Stromal Interaction Molecule 1
Thrombus
Growth Disorders
Mice, Knockout
Membrane Glycoproteins
Voltage-dependent calcium channel
business.industry
Endoplasmic reticulum
Brief Definitive Report
STIM1
Thrombosis
medicine.disease
Sarcoplasmic Reticulum
Endocrinology
Brief Definitive Reports
Calcium
Calcium Channels
business
Subjects
Details
- ISSN :
- 15409538
- Volume :
- 205
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- The Journal of experimental medicine
- Accession number :
- edsair.doi.dedup.....378adf03eafcb9f351df3afd3beff1d9