Effects of ACE inhibitor and AT1 blocker on dystrophin-related proteins and calpain in failing heart.

Abstract

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-I-converting enzyme inhibitor (ACEI) trandolapril (Tra) or an angiotensin II type 1 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 1 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 microM 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.

• Authors: Masaya Takahashi, Kouichi Tanonaka, Hiroyuki Yoshida, Ryo Oikawa, Miki Koshimizu, Takuya Daicho, Teruhiko Toyo-Oka, Satoshi Takeo
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 65 Issue 2 Pg. 356-65 (Feb 01 2005) ISSN: 0008-6363 [Print] England
• PMID: 15639474 (Publication Type: Journal Article)

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Benzimidazoles
• Biphenyl Compounds
• Indoles
• Protein Isoforms
• Receptor, Angiotensin, Type 1
• Sarcoglycans
• Tetrazoles
• trandolapril
• Calpain
• candesartan

Topics

• Angiotensin-Converting Enzyme Inhibitors (pharmacology)
• Animals
• Benzimidazoles (pharmacology)
• Biphenyl Compounds
• Blotting, Western (methods)
• Calpain (analysis, metabolism)
• Cytosol (chemistry, metabolism)
• Heart Failure (metabolism)
• Hemodynamics (drug effects)
• Indoles (pharmacology)
• Male
• Models, Animal
• Myocardium (chemistry, metabolism)
• Protein Isoforms (chemistry, metabolism)
• Rats
• Rats, Wistar
• Receptor, Angiotensin, Type 1 (drug effects)
• Reverse Transcriptase Polymerase Chain Reaction
• Sarcoglycans (analysis, metabolism)
• Tetrazoles (pharmacology)