Post-infarction heart failure in the rat is associated with distinct alterations in cardiac myocyte molecular phenotype.
The myocardial molecular and cellular responses to hemodynamic and other 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 undertaken to test the hypothesis that post-infarction heart failure and remodeling in the rat is associated with a distinct myocyte molecular phenotype. To address this question, hemodynamic measurements were performed in vivo; and myocytes isolated from the non-infarcted myocardium 1 day, 1 week, and 6 weeks post-coronary artery ligation in post-infarct rats and sham controls. Myocyte size, mRNA levels for immediate early genes, contractile proteins, and sarcoplasmic reticulum Ca2+-ATPase (SERCA) and phospholamban were assayed by Northern analyses, and SERCA and phospholamban proteins were examined by Western blotting. Hemodynamic evidence of heart failure was present at all post-infarct time points. Myocyte size was increased significantly at 6 weeks. c-myc expression was increased at 1 day and 1 week in the infarcted rats, but returned to baseline by 6 weeks. Atrial natriuretic peptide and VEGF mRNAs were elevated at 1 and 6 weeks. Both beta-myosin heavy chain and skeletal alpha-actin expression were increased at all post-MI time points. In contrast, neither changes in the expression of the calcium-handling proteins (SERCA and phospholamban) were not observed, nor was there a change in TGFbeta1 or TGFbeta3. These results demonstrate that in rats with post-MI heart failure, there was an immediate induction of the fetal/embryonic transcriptional gene program which preceded myocyte hypertrophy and appeared to persist longer than in pressure-overload models. In further contrast to pressure-overload, expression of sarcoplasmic reticulum Ca2+-ATPase and phospholamban, was not altered despite a comparable degree of cellular hypertrophy and more severe hemodynamic decompensation. These findings suggest that there may be important differences in the regulatory mechanisms underlying these two forms of myocardial hypertrophy and heart failure.
Yue
P
P
Department of Medicine, University of California, San Francisco, CA, USA.
Long
C S
CS
Austin
R
R
Chang
K C
KC
Simpson
P C
PC
Massie
B M
BM
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D048429:Cell Size; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D016762:Genes, fos; D016259:Genes, myc; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000150:complications* / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000473:pathology*; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099211:Phospholamban
D000199:Actins; D009320:Atrial Natriuretic Factor; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D003285:Contractile Proteins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D018995:Myosin Heavy Chains; D012313:RNA; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099211:Phospholamban