In vivo administration of calpeptin attenuates calpain activation and cardiomyocyte loss in pressure-overloaded feline myocardium
- 1 July 2008
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 295 (1), H314-H326
- https://doi.org/10.1152/ajpheart.00085.2008
Abstract
Calpain activation is linked to the cleavage of several cytoskeletal proteins and could be an important contributor to the loss of cardiomyocytes and contractile dysfunction during cardiac pressure overload (PO). Using a feline right ventricular (RV) PO model, we analyzed calpain activation during the early compensatory period of cardiac hypertrophy. Calpain enrichment and its increased activity with a reduced calpastatin level were observed in 24- to 48-h-PO myocardium, and these changes returned to basal level by 1 wk of PO. Histochemical studies in 24-h-PO myocardium revealed the presence of TdT-mediated dUTP nick-end label (TUNEL)-positive cardiomyocytes, which exhibited enrichment of calpain and gelsolin. Biochemical studies showed an increase in histone H2B phosphorylation and cytoskeletal binding and cleavage of gelsolin, which indicate programmed cardiomyocyte cell death. To test whether calpain inhibition could prevent these changes, we administered calpeptin (0.6 mg/kg iv) by bolus injections twice, 15 min before and 6 h after induction of 24-h PO. Calpeptin blocked the following PO-induced changes: calpain enrichment and activation, decreased calpastatin level, caspase-3 activation, enrichment and cleavage of gelsolin, TUNEL staining, and histone H2B phosphorylation. Although similar administration of a caspase inhibitor, N-benzoylcarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VD-fmk), blocked caspase-3 activation, it did not alleviate other aforementioned changes. These results indicate that biochemical markers of cardiomyocyte cell death, such as sarcomeric disarray, gelsolin cleavage, and TUNEL-positive nuclei, are mediated, at least in part, by calpain and that calpeptin may serve as a potential therapeutic agent to prevent cardiomyocyte loss and preserve myocardial structure and function during cardiac hypertrophy.Keywords
This publication has 70 references indexed in Scilit:
- Calpain inhibition attenuates right ventricular contractile dysfunction after acute pressure overloadJournal of Molecular and Cellular Cardiology, 2008
- Calpain-dependent calpastatin cleavage regulates caspase-3 activation during apoptosis of Jurkat T cells induced by Entamoeba histolyticaInternational Journal for Parasitology, 2007
- Mechanisms of Disease: apoptosis in heart failure—seeing hope in deathNature Clinical Practice Cardiovascular Medicine, 2006
- Acidosis Causes Endoplasmic Reticulum Stress and Caspase-12-Mediated Astrocyte DeathJournal of Cerebral Blood Flow & Metabolism, 2005
- Differential degradation of calpastatin by μ‐ and m‐calpain in Ca2+‐enriched human neuroblastoma LAN‐5 cellsFEBS Letters, 2000
- Gelsolin Inhibits Apoptosis by Blocking Mitochondrial Membrane Potential Loss and Cytochrome c ReleasePublished by Elsevier BV ,2000
- Calpain and caspase: can you tell the difference?, by Kevin K.W. Wang: Vol. 23, pp. 20–26Trends in Neurosciences, 2000
- BASIC DETERMINANTS OF MYOCARDIAL HYPERTROPHY: A Review of Molecular MechanismsAnnual Review of Medicine, 1997
- Load effects on gene expression during cardiac hypertrophyJournal of Molecular and Cellular Cardiology, 1995
- Exogenous gelsolin binds to sarcomeric thin filaments without severingCell Motility, 1995