| First Author | Liu F | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 42 | Pages | 30672-81 |
| PubMed ID | 24014035 | Mgi Jnum | J:204912 |
| Mgi Id | MGI:5543724 | Doi | 10.1074/jbc.M113.472688 |
| Citation | Liu F, et al. (2013) Mitochondrially mediated integrin alphaIIbbeta3 protein inactivation limits thrombus growth. J Biol Chem 288(42):30672-81 |
| abstractText | When platelets are strongly stimulated, a procoagulant platelet subpopulation is formed that is characterized by phosphatidylserine (PS) exposure and epitope modulation of integrin alphaIIbbeta3 or a loss of binding of activation-dependent antibodies. Mitochondrial permeability transition pore (mPTP) formation, which is essential for the formation of procoagulant platelets, is impaired in the absence of cyclophilin D (CypD). Here we investigate the mechanisms responsible for these procoagulant platelet-associated changes in integrin alphaIIbbeta3 and the physiologic role of procoagulant platelet formation in the regulation of platelet aggregation. Among strongly stimulated adherent platelets, integrin alphaIIbbeta3 epitope changes, mPTP formation, PS exposure, and platelet rounding were closely associated. Furthermore, platelet mPTP formation resulted in a decreased ability to recruit additional platelets. In the absence of CypD, integrin alphaIIbbeta3 function was accentuated in both static and flow conditions, and, in vivo, a prothrombotic phenotype occurred in mice with a platelet-specific deficiency of CypD. CypD-dependent proteolytic events, including cleavage of the integrin beta3 cytoplasmic domain, coincided closely with integrin alphaIIbbeta3 inactivation. Calpain inhibition blocked integrin beta3 cleavage and inactivation but not mPTP formation or PS exposure, indicating that integrin inactivation and PS exposure are mediated by distinct pathways subsequent to mPTP formation. mPTP-dependent alkalinization occurred in procoagulant platelets, suggesting a possible alternative mechanism for enhancement of calpain activity in procoagulant platelets. Together, these results indicate that, in strongly stimulated platelets, mPTP formation initiates the calpain-dependent cleavage of integrin beta3 and associated regulatory proteins, resulting in integrin alphaIIbbeta3 inactivation, and demonstrate a novel CypD-dependent negative feedback mechanism that limits platelet aggregation and thrombotic occlusion. |
