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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on October 7, 2005; DOI: 10.1124/jpet.105.093898

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Received for publication August 10, 2005.
Revised October 6, 2005.
Accepted for publication October 6, 2005.

Dominant role for calpain in thromboxane-induced neuromicrovascular endothelial cytotoxicity

Christiane Quiniou 1, Florian Sennlaub 2, Martin H. Beauchamp 1, Daniela Checchin 3, Isabelle Lahaie 4, Sonia Brault 3, Fernand Gobeil Jr. 5, Mirna Sirinyan 3, Amna Kooli 3, Pierre Hardy 6, Alexei Pshezhetsky 6, Sylvain Chemtob 3*

1 University of Montreal 2 Univeristy of Montreal, INSERM 3 McGill University 4 Centre de Recherche de l'Hopital Ste-Justine 5 Universite de Sherbrooke 6 Universite de Montreal

* Address correspondence to: E-mail: sylvain.chemtob{at}umontreal.ca

Abstract

TXA2 is an important lipid mediator generated during oxidative stresses and implicated in ischemic neural injury. This autacoid was recently shown to partake in this process by directly inducing endothelial cytotoxicity. We explored the mechanisms for this TXA2-evoked neural microvascular endothelial cell death. Stable TXA2 mimetics U46619 (as well as I-BOP) induced a retinal microvascular degeneration in rat pups in vivo, on porcine retinal explants ex vivo, and death of porcine brain endothelial cells (in culture); TXA2-dependence of these effects were corroborated by antagonism using the selective TXA2 receptor blocker L670596. In all cases neurovascular endothelial cell death was prevented by pan-calpain and specific m-calpain inhibitors, but not by caspase 3 or pan-caspase inhibitors. Correspondingly, TXA2 (mimetics) augmented generation of known active m-calpain (but not µ-calpain) form, and increased the activity of m-calpain (cleavage of fluorogenic substrate Suc-LLVY-AMC and of {alpha}-spectrin into specific fragments) but not of pan-caspase or specific caspase 3 (respectively, using SR-VAD-fmk and detecting its active 17 and 12 kDa fragments). Interestingly, these effects were PLC-dependent (associated with increase in IP3 and inhibited by PLC blocker U73122) and required calcium but were not associated with increased intracellular calcium. U46619-induced calpain activation resulted in translocation of Bax to the mitochondria, loss of polarization of the latter (using potentiometric probe JC-1) and in turn release of cytochrome C into the cytosol and depletion of cellular ATP; these effects were all blocked by calpain inhibitors. Overall, this work identifies (specifically) m-calpain as a dominant protease in TXA2-induced neurovascular endothelial cell death.


Key words: calpain, cell death, endothelium, oxydative stress, thromboxane, vasoobliteration


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[Abstract] [Full Text] [PDF]


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