Infarct size is increased in female post-MI rats treated with rapamycin.
Rapamycin represents a recognized drug-based therapeutic approach to treat cardiovascular disease. However, at least in the female heart, rapamycin may suppress the recruitment of putative signalling events conferring cardioprotection. The present study tested the hypothesis that rapamycin-sensitive signalling events contributed to the cardioprotective phenotype of the female rat heart after an ischemic insult. Rapamycin (1.5 mg/kg) was administered to adult female Sprague-Dawley rats 24 h after complete coronary artery ligation and continued for 6 days. Rapamycin abrogated p70S6K phosphorylation in the left ventricle of sham rats and the noninfarcted left ventricle (NILV) of 1-week postmyocardial-infarcted (MI) rats. Scar weight (MI 0.028 +/- 0.006, MI+rapamycin 0.064 +/- 0.004 g) and surface area (MI 0.37 +/- 0.08, MI+rapamycin 0.74 +/- 0.03 cm2) were significantly larger in rapamycin-treated post-MI rats. In the NILV of post-MI female rats, rapamycin inhibited the upregulation of eNOS. Furthermore, the increased expression of collagen and TGF-beta3 mRNAs in the NILV were attenuated in rapamycin-treated post-MI rats, whereas scar healing was unaffected. The present study has demonstrated that rapamycin-sensitive signalling events were implicated in scar formation and reactive fibrosis. Rapamycin-mediated suppression of eNOS and TGF-beta3 mRNA in post-MI female rats may have directly contributed to the larger infarct and attenuation of the reactive fibrotic response, respectively.
Lajoie
Claude
C
Université du Québec de Trois-Rivières, Trois-Rivières, QC, Canada.
El-Helou
Viviane
V
Proulx
Cindy
C
Clément
Robert
R
Gosselin
Hugues
H
Calderone
Angelino
A
D000818:Animals; D015153:Blotting, Western; D002921:Cicatrix / Q000473:pathology* / Q000517:prevention & control; D003094:Collagen / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology* / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D053782:Transforming Growth Factor beta3 / Q000096:biosynthesis; D020257:Ventricular Remodeling / Q000187:drug effects*
D053782:Transforming Growth Factor beta3; D003094:Collagen; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus