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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1257-1265.
Prepublished online as a Blood First Edition Paper on November 7, 2007; DOI 10.1182/blood-2007-05-092684.
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Submitted May 29, 2007
Accepted October 27, 2007
Critical role for the mitochondrial permeability transition pore and cyclophilin D in platelet activation and thrombosis
Shawn M Jobe*, Katina M Wilson, Lorie Leo, Alejandro Raimondi, Jeffery D Molkentin, Steven R Lentz, and Jorge Di Paola
Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, United States
Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United States
Department of Pediatrics, University of Cincinnati, Cincinnati, OH, United States
Veteran Affairs Medical Center, Iowa City, IA, United States
* Corresponding author; email: shawn.jobe{at}emory.edu.
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 (  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 H2O2, 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.
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