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Blood. 2008 Feb 1;111(3):1257-65. Epub 2007 Nov 7.

Critical role for the mitochondrial permeability transition pore and cyclophilin D in platelet activation and thrombosis.

Author information

1
Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, USA. shawn.jobe@emory.edu

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 (Deltapsi(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.

PMID:
17989312
PMCID:
PMC2214770
DOI:
10.1182/blood-2007-05-092684
[Indexed for MEDLINE]
Free PMC Article
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