Journal article
Critical role for the mitochondrial permeability transition pore and cyclophilin D in platelet activation and thrombosis
Blood, Vol.111(3), pp.1257-1265
Hemostasis, Thrombosis, and Vascular Biology
02/01/2008
DOI: 10.1182/blood-2007-05-092684
PMCID: PMC2214770
PMID: 17989312
Abstract
Many of the cellular responses that occur in activated platelets resemble events that take place following activation of cell-death pathways in nucleated cells. We tested the hypothesis that formation of the mitochondrial permeability transition pore (MPTP), a key signaling event during cell death, also plays a critical role in platelet activation. Stimulation of murine platelets with thrombin plus the glycoprotein VI agonist convulxin resulted in a rapid loss of mitochondrial transmembrane potential (Δψ
m
) in a subpopulation of activated platelets. In the absence of cyclophilin D (CypD), an essential regulator of MPTP formation, murine platelet activation responses were altered. CypD-deficient platelets exhibited defects in phosphatidylserine externalization, high-level surface fibrinogen retention, membrane vesiculation, and procoagulant activity. Also, in CypD-deficient platelet-rich plasma, clot retraction was altered. Stimulation with thrombin plus H
2
O
2
, a known activator of MPTP formation, also increased high-level surface fibrinogen retention, phosphatidylserine externalization, and platelet procoagulant activity in a CypD-dependent manner. In a model of carotid artery photochemical injury, thrombosis was markedly accelerated in CypD-deficient mice. These results implicate CypD and the MPTP as critical regulators of platelet activation and suggest a novel CypD-dependent negative-feedback mechanism regulating arterial thrombosis.
Details
- Title: Subtitle
- Critical role for the mitochondrial permeability transition pore and cyclophilin D in platelet activation and thrombosis
- Creators
- Shawn M Jobe - Departments ofKatina M Wilson - Internal Medicine, University of Iowa Carver College of Medicine, Iowa CityLorie Leo - Internal Medicine, University of Iowa Carver College of Medicine, Iowa CityAlejandro Raimondi - Departments ofJeffery D Molkentin - Department of Pediatrics, University of Cincinnati, OH; andSteven R Lentz - Internal Medicine, University of Iowa Carver College of Medicine, Iowa CityJorge Di Paola - Departments of
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.111(3), pp.1257-1265
- Publisher
- American Society of Hematology
- Series
- Hemostasis, Thrombosis, and Vascular Biology
- DOI
- 10.1182/blood-2007-05-092684
- PMID
- 17989312
- PMCID
- PMC2214770
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Language
- English
- Date published
- 02/01/2008
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094318002771
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