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Calpain inhibition prevents pacing-induced cellular remodeling in a HL-1 myocyte model for atrial fibrillation

Calpain inhibition prevents pacing-induced cellular remodeling in a HL-1 myocyte model for atrial... AbstractObjective: Atrial fibrillation (AF) is a progressive disease. Previously, clinical and animal experimental studies in AF revealed a variety of myocyte remodeling processes including L-type Ca2+ channel reduction and structural changes, which finally result in electrical remodeling and contractile dysfunction. There are indications that myocyte remodeling is mediated by Ca2+ overload induced calpain activation. To study in more detail the mechanisms underlying myocyte remodeling and to develop strategies for drug-interference, we utilised a paced cell model for AF. Methods and results: HL-1 atrial myocytes were subjected to a 10 times increase in rate over basal values by electrical field stimulation at 5 Hz. It was found that 24-h pacing reduced plasmalemmal levels of L-type Ca2+ channel α1C subunit by −72% compared to controls. No changes in amount of the potassium channel subunits Kv4.3 and Kv1.5 were found. Pacing also induced marked structural changes; myolysis and nuclear condensation, paralleled by a 14-fold increase in calpain activity. The pacing-induced reduction of L-type Ca2+ channel protein was fully prevented by treatment with verapamil, the active stereoisomer of methoxyverapamil D600, the calpain inhibitors PD150606 and E64d, and LaCl3. Interestingly, PD150606, E64d and LaCl3, but not (methoxy)verapamil, prevented structural changes. Conclusions: Paced HL-1 atrial myocytes undergo myocyte remodeling similar to that found in myocytes from patients with AF. Calcium influx independent of the L-type Ca2+ channel and subsequent activation of calpain represent key features in the progression towards overt structural changes. Calpain inhibition may therefore represent a useful lead for therapeutic intervention in AF. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cardiovascular Research Oxford University Press

Calpain inhibition prevents pacing-induced cellular remodeling in a HL-1 myocyte model for atrial fibrillation

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References (43)

Publisher
Oxford University Press
Copyright
Copyright © 2004, European Society of Cardiology
ISSN
0008-6363
eISSN
1755-3245
DOI
10.1016/j.cardiores.2004.02.007
pmid
15158144
Publisher site
See Article on Publisher Site

Abstract

AbstractObjective: Atrial fibrillation (AF) is a progressive disease. Previously, clinical and animal experimental studies in AF revealed a variety of myocyte remodeling processes including L-type Ca2+ channel reduction and structural changes, which finally result in electrical remodeling and contractile dysfunction. There are indications that myocyte remodeling is mediated by Ca2+ overload induced calpain activation. To study in more detail the mechanisms underlying myocyte remodeling and to develop strategies for drug-interference, we utilised a paced cell model for AF. Methods and results: HL-1 atrial myocytes were subjected to a 10 times increase in rate over basal values by electrical field stimulation at 5 Hz. It was found that 24-h pacing reduced plasmalemmal levels of L-type Ca2+ channel α1C subunit by −72% compared to controls. No changes in amount of the potassium channel subunits Kv4.3 and Kv1.5 were found. Pacing also induced marked structural changes; myolysis and nuclear condensation, paralleled by a 14-fold increase in calpain activity. The pacing-induced reduction of L-type Ca2+ channel protein was fully prevented by treatment with verapamil, the active stereoisomer of methoxyverapamil D600, the calpain inhibitors PD150606 and E64d, and LaCl3. Interestingly, PD150606, E64d and LaCl3, but not (methoxy)verapamil, prevented structural changes. Conclusions: Paced HL-1 atrial myocytes undergo myocyte remodeling similar to that found in myocytes from patients with AF. Calcium influx independent of the L-type Ca2+ channel and subsequent activation of calpain represent key features in the progression towards overt structural changes. Calpain inhibition may therefore represent a useful lead for therapeutic intervention in AF.

Journal

Cardiovascular Research – Oxford University Press

Published: Jun 1, 2004

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