Objectives: Genetic depletion of dystrophin-related protein (DRP) complex causes cardiomyopathy in animals and humans. We found in a previous study that some types of DRP were degraded and that calpain content was increased in rats with non-genetically induced heart failure. The present study was aimed at examining the effects of an angiotensin-1-converting enzyme inhibitor (ACEI) trandolapril (Tra) or an angiotensin 11 type I receptor blocker (ARB) candesartan (Can), both of which are known to improve the pathophysiology of chronic heart failure (CHF) on degradation of DRP in failing hearts.
Methods: Coronary artery-ligated (CAL) and sham-operated rats (Sham rats) were treated orally with 3 mg/kg/day trandolapril (Tra) or I mg/kg/day candesartan (Can) from the 2nd to 8th week after surgery.
Results: Hemodynamic parameters of CAL rats at the 8th week after CAL (8w-CAL) indicated heart failure. alpha-Sarcoglycan (SG) and dystrophin in the surviving left ventricle (surviving LV) of 8w-CAL rats decreased, whereas beta-, gamma-, and delta-SGs remained unchanged. Calcium-activated neutral proteases mu-calpain and m-calpain increased in the surviving LV at the 8th week of postmyocardial infarction. Proteolytic activity in the presence of 5 mM Ca2+ markedly increased at the 2nd and 8th weeks, whereas 50 muM Ca2+ slightly but significantly increased proteolysis of casein. Tra or Can treatment improved the hemodynamic parameters, attenuated changes in alpha-SG and dystrophin, and reversed both calpain contents and activities of the failing heart back to sham levels.
Conclusion: These results suggest that attenuation in calpain-induced degradation of DRP complex is a possible mechanism for the Tra- or Can-mediated improvement of the pathogenesis of CHF following myocardial infarction. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.