POSTINFARCTION HEART-FAILURE IN THE RAT IS ASSOCIATED WITH DISTINCT ALTERATIONS IN CARDIAC MYOCYTE MOLECULAR PHENOTYPE

The myocardial molecular and cellular responses to hemodynamic and oth er hypertrophic stimuli have been characterized extensively, but less is known of the alterations in gene expression during the evolution of heart failure following myocardial infarction, and specifically those affecting the cardiac myocytes. Therefore, the present study was unde rtaken to test the hypothesis that post-infarction heart failure and r emodeling in the rat is associated with a distinct myocyte molecular p henotype. To address this question, hemodynamic measurements were perf ormed in vivo; and myocytes isolated from the non-infarcted myocardium 1 day, 1 week, and 6 weeks post-coronary artery ligation in post-infa rct rats and sham controls, Myocyte size, mRNA levels for immediate ea rly genes, contractile proteins, and sarcoplasmic reticulum Ca2+-ATPas e (SERCA) and phospholamban were assayed by Northern analyses, and SER CA and phospholamban proteins were examined by Western blotting. Hemod ynamic evidence of heart failure was present at all post-infarct time points. Mycocyte size was increased significantly at 6 weeks, c-myc ex pression was increased at 1 day and 1 week in the infarcted rats, but returned to baseline by 6 weeks. Atrial natriuretic peptide and VEGF m RNAs were elevated at 1 and 6 weeks. Both beta-myosin heavy chain and skeletal alpha-actin expression were increased at all post-MI time poi nts. In contrast, neither changes in the expression of the calcium-han dling proteins (SERCA and phospholamban) were not observed, nor was th ere a change in TGF beta(1) or TGF beta(3). These results demonstrate that in rats with post-MI heart failure, there was an immediate induct ion of the fetal/embryonic transcriptional gene program which preceded myocyte hypertrophy and appeared to persist longer than in pressure-o verload models. In further contrast to pressure-overload, expression o f sarcoplasmic reticulum Ca2+-ATPase and phospholamban, was not altere d despite a comparable degree of cellular hypertrophy and more severe hemodynamic decompensation. These findings suggest that there may be i mportant differences in the regulatory mechanisms underlying these two forms of myocardial hypertrophy and heart failure. (C) 1998 Academic Press