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Updated: Jun 3, 2025
Post-Myocardial Infarction Heart Failure in Closed-chest Coronary Occlusion/Reperfusion Model in Göttingen Minipigs and Landrace Pigs
Published on: April 17, 2021
Restoration effect of chemically modified microRNA-143-3p on acute myocardial infarction in animal models
Shingo Minatoguchi1, Nobuhiko Sugito2, Kazuki Heishima2
1Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.
Abstract:
We investigated whether miR143#12, a synthesized chemically modified miR-143-3p derivative, exerts therapeutic effects on acute myocardial infarction (AMI). Sprague-Dawley rats and Japanese white rabbits underwent 30 min of coronary occlusion followed by 2 weeks of reperfusion. The rat AMI model was intravenously administered with control miRNA (9 μg/kg), 3 μg/kg or 9 μg/kg of miR143#12 1 h after reperfusion, while the rabbit AMI model was intravenously administered with control miRNA (9 μg/kg) or 9 μg/kg of miR143#12. In the rat and rabbit AMI models, 9 μg/kg of miR143#12 significantly reduced infarct sizes and significantly improved cardiac function including LVEF and LVFS at 2 weeks. The tissue miR143 levels in infarct areas significantly decreased after AMI in both models. Electron microscopic study and immunohistochemistry suggested that miR143#12 suppressed autophagic cell death caused by AMI and induced neoangiogenesis in the infarct border. In cultured rat H9c2 cells, miR143#12 significantly inhibited H2O2-induced autophagic cell death by decreasing ROS levels and increased viable cell numbers more than the control by silencing COX-1, -2, and ATG7. Replacement treatment with miR143#12 in the infarct areas, where the expression levels of miR143 were significantly decreased, has a beneficial effect on AMI by silencing COX-1 and -2.
Insights
A novel miR-143-3p derivative, miR143#12, shows therapeutic potential for acute myocardial infarction (AMI). It reduces infarct size, improves cardiac function, and suppresses cell death by targeting key genes.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Regenerative Medicine
Background:
- Acute myocardial infarction (AMI) leads to significant cardiac damage and impaired function.
- MicroRNAs (miRNAs) play crucial roles in cardiac pathophysiology, with miR-143-3p levels decreasing post-AMI.
- There is a need for novel therapeutic strategies to mitigate myocardial damage and promote recovery after AMI.
Purpose of the Study:
- To investigate the therapeutic efficacy of miR143#12, a chemically modified miR-143-3p derivative, in preclinical models of acute myocardial infarction.
- To elucidate the underlying mechanisms by which miR143#12 exerts its protective effects on the infarcted heart.
Main Methods:
- Establishment of rat and rabbit models of acute myocardial infarction (AMI) via coronary artery occlusion and reperfusion.
- Intravenous administration of miR143#12 or control miRNA at varying doses post-reperfusion.
- Assessment of cardiac function (LVEF, LVFS), infarct size, and tissue miR143 levels.
- In vitro studies using H9c2 cells to evaluate the effects of miR143#12 on oxidative stress and cell death, involving gene silencing (COX-1, -2, ATG7).
- Electron microscopy and immunohistochemistry to analyze cellular changes and neovascularization.
Main Results:
- Administration of 9 μg/kg miR143#12 significantly reduced infarct size and improved cardiac function (LVEF, LVFS) in both rat and rabbit AMI models.
- miR143#12 treatment suppressed autophagic cell death and promoted neoangiogenesis in the infarct border zone.
- In vitro, miR143#12 inhibited H2O2-induced autophagic cell death in H9c2 cells by decreasing ROS levels and increasing cell viability, partly through silencing COX-1, -2, and ATG7.
- Significantly decreased endogenous miR143 levels in infarct areas post-AMI were observed in both animal models.
Conclusions:
- miR143#12 demonstrates significant therapeutic benefits in preclinical models of AMI, improving cardiac function and reducing infarct size.
- The protective effects of miR143#12 are attributed to the suppression of autophagic cell death and induction of neoangiogenesis.
- miR143#12 acts by silencing key genes including COX-1, COX-2, and ATG7, offering a promising novel therapeutic agent for AMI treatment.
