Calcium channel blockade limits transcriptional, translational and functional up-regulation of the cardiac calpain system after myocardial infarction

Eur J Pharmacol. 2002 Oct 18;453(1):99-109. doi: 10.1016/s0014-2999(02)02384-1.

Abstract

Abnormal Ca(2+) inward current through cardiac Ca(2+) channels during ischemia has been shown to be an initial signal for activation of myocardial Ca(2+)-dependent enzymes. This study investigated the contribution of cardiac L- and T-type Ca(2+) channels in the calpain-mediated myocardial damage following myocardial infarction. Myocardial infarction was induced by permanent ligation of the left coronary artery. Infarcted rats were orally treated with placebo, amlodipine (L-channel blockade; 4 mg/kg/day) or mibefradil (L-/T-channel blockade; 10 mg/kg/day) beginning 7 days before induction of myocardial infarction. Gene expression, protein levels and enzyme activity of calpains I and II were measured 1, 3, 7 and 14 days postcoronary occlusion in the noninfarcted and infarcted myocardium. Infarct size, left ventricular dilation and interstitial collagen volume fraction were determined in picrosirius red-stained hearts. Myocardial infarction induced an up-regulation of calpain I mRNA, protein and activity in the noninfarcted myocardium (maximum 14 days postinfarction), whereas mRNA, protein and activity of calpain II were maximally increased in the infarcted myocardium 3 days postinfarction. Fourteen days postinfarction, infarct size was 49%, the left ventricle was dilated and interstitial collagen volume fraction was increased. Amlodipine-inhibited mRNA, protein and activity up-regulation of calpain I decreased interstitial collagen volume fraction and infarct size. Mibefradil-attenuated mRNA, protein and activity up-regulation of calpain II at all four time points measured and of calpain I at 7 and 14 days postinfarction reduced infarct size and prevented left ventricular dilation. Infarction-induced cardiac hypertrophy was accompanied by an up-regulation of calpain I, whereas calpain II was up-regulated in the infarcted myocardium. Cardiac L- and T-type Ca(2+) channel blockade differentially reduced postinfarction remodeling associated with selective inhibition of cardiac calpains I and II, respectively.

MeSH terms

  • Animals
  • Calcium Channel Blockers / pharmacology*
  • Calpain / biosynthesis*
  • Calpain / genetics
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Male
  • Myocardial Infarction / enzymology*
  • Myocardial Infarction / genetics
  • Myocardium / enzymology
  • Protein Biosynthesis / drug effects*
  • Protein Biosynthesis / physiology
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Rats
  • Rats, Wistar
  • Transcription, Genetic / drug effects*
  • Transcription, Genetic / physiology
  • Up-Regulation / drug effects*
  • Up-Regulation / physiology

Substances

  • Calcium Channel Blockers
  • RNA, Messenger
  • Calpain