Infarct size is increased in female post-MI rats treated with rapamycin
Claude Lajoie1, Viviane El-Helou, Cindy Proulx
1Université du Québec de Trois-Rivières, Trois-Rivières, QC, Canada.
Abstract:
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.
Insights
Rapamycin treatment worsened heart attack outcomes in female rats by suppressing protective signaling pathways. This drug impaired the heart's natural repair mechanisms, leading to larger infarcts and altered fibrotic responses.
Area of Science:
- Cardiovascular Disease Research
- Pharmacology
- Molecular Biology
Background:
- Rapamycin is a known therapeutic for cardiovascular disease.
- However, its effects on cardioprotection in the female heart are not fully understood.
- Rapamycin may inhibit protective signaling pathways in the female heart.
Purpose of the Study:
- To investigate the role of rapamycin-sensitive signaling in the cardioprotective phenotype of the female rat heart post-ischemic insult.
- To test the hypothesis that these signaling events contribute to heart protection.
Main Methods:
- Adult female Sprague-Dawley rats underwent coronary artery ligation to induce myocardial infarction (MI).
- Rapamycin (1.5 mg/kg) was administered 24 hours post-MI and continued for 6 days.
- Key signaling molecules (p70S6K, eNOS), scar characteristics (weight, surface area), and gene expression (collagen, TGF-beta3) were analyzed in heart tissue.
Main Results:
- Rapamycin treatment significantly increased scar weight and surface area in post-MI female rats.
- It abrogated p70S6K phosphorylation and inhibited the upregulation of eNOS in the non-infarcted left ventricle.
- Rapamycin attenuated increased collagen and TGF-beta3 mRNA expression in the non-infarcted left ventricle.
Conclusions:
- Rapamycin-sensitive signaling events are implicated in scar formation and reactive fibrosis following myocardial infarction in female rats.
- Suppression of eNOS and TGF-beta3 mRNA by rapamycin may contribute to larger infarct size and altered fibrotic response.
- These findings suggest rapamycin may counteract endogenous cardioprotective mechanisms in the female heart post-MI.
