Document Detail


Calpain translocation and activation as pharmacological targets during myocardial ischemia/reperfusion.
MedLine Citation:
PMID:  20211186     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Calpains contribute to reperfusion-induced myocardial cell death. However, it remains controversial whether its activation occurs during ischemia or reperfusion. We investigated the regulation and time-course of calpain activation secondary to transient ischemia and the efficacy of its inhibition at reperfusion as a therapeutic strategy to limit infarct size. In isolated rat hearts (Sprague-Dawley), ischemia induced a time-dependent translocation of m-calpain to the membrane that was not associated with calpain activation as assessed by proteolysis of its substrate alpha-fodrin. Translocation of calpain was dependent on Ca(2+) entry through reverse mode Na(+)/Ca(2+)-exchange and was independent of acidosis. Calpain activation occurred during reperfusion, but only after intracellular pH (pHi) normalization, and was not prevented by inhibiting its translocation during ischemia with methyl-beta-cyclodextrin. The intravenous infusion of MDL-28170 in an in vivo rat model with transient coronary occlusion during the first minutes of reperfusion resulted in a reduction of infarct size (43.9+/-3.9% vs. 60.2+/-4.7, P=0.046, n=18) and alpha-fodrin degradation. These results suggest that (1) Ca(2+)-induced calpain translocation to the membrane during ischemia is independent of its activation, (2) intracellular acidosis inhibits calpain activation during ischemia and pHi normalization allows activation upon reperfusion, and (3) calpain inhibition at the time of reperfusion appears as a potentially useful strategy to limit infarct size.
Authors:
Víctor Hernando; Javier Inserte; Carmem Luíza Sartório; Víctor M Parra; Marcos Poncelas-Nozal; David Garcia-Dorado
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-06
Journal Detail:
Title:  Journal of molecular and cellular cardiology     Volume:  49     ISSN:  1095-8584     ISO Abbreviation:  J. Mol. Cell. Cardiol.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-06-14     Completed Date:  2010-09-09     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0262322     Medline TA:  J Mol Cell Cardiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  271-9     Citation Subset:  IM    
Affiliation:
Servei de Cardiologia, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcium-Binding Proteins / metabolism
Calpain / antagonists & inhibitors,  metabolism*
Cell Death / drug effects
Enzyme Activation / drug effects
Hemodynamics / drug effects
Hydrogen-Ion Concentration
Intracellular Space / drug effects,  metabolism
Male
Myocardial Infarction / complications,  pathology,  physiopathology
Myocardial Reperfusion Injury / complications,  drug therapy*,  enzymology*,  physiopathology
Myocardium / enzymology,  pathology
Protease Inhibitors / pharmacology
Protein Transport / drug effects
Rats
Rats, Sprague-Dawley
Chemical
Reg. No./Substance:
0/Calcium-Binding Proteins; 0/Protease Inhibitors; 79079-11-1/calpastatin; EC 3.4.22.-/Calpain; EC 3.4.22.-/m-calpain

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