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In Vivo Nanovector Delivery of a Heart-specific MicroRNA-sponge
Published on: June 15, 2018
MicroRNA-145 repairs infarcted myocardium by accelerating cardiomyocyte autophagy
Kenshi Higashi1, Yoshihisa Yamada1, Shingo Minatoguchi2
1Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan; and.
Abstract:
We investigated whether microRNA-145 (miR-145) has a cardioprotective effect in a rabbit model of myocardial infarction (MI) and in H9c2 rat cardiomyoblasts. Rabbits underwent 30 min of coronary occlusion, followed by 2 days or 2 wk of reperfusion. Control microRNA (control group; 2.5 nmol/kg, n = 10) or miR-145 (miR-145 group, 2.5 nmol/kg, n = 10) encapsulated in liposomes was intravenously administered immediately after the start of reperfusion. H9c2 rat cardiomyoblasts were transfected with miR-145. The MI size was significantly smaller in the miR-145 group than in the control group at 2 days and 2 wk post-MI. miR-145 had improved the cardiac function and remodeling at 2 wk post-MI. These effects were reversed by chloroquine. Western blot analysis showed that miR-145 accelerated the transition of LC3B I to II and downregulated p62/SQSTM1 at 2 days or 2 wk after MI, but not at 4 wk, and activated Akt in the ischemic area at 2 days after MI. miR-145 inhibited the growth of H9c2 cells, accelerated the transition of LC3B I to II, and increased phosphorylated Akt in the H9c2 cells at 2 days after miR-145 transfection. Antagomir-145 significantly abolished the morphological change, the transition of LC3B I to II, and the increased phosphorylated Akt induced by miR-145 in H9c2 cells. We determined fibroblast growth factor receptor substrate 2 mRNA to be a target of miR-145, both in an in vivo model and in H9c2 cells. In conclusion, post-MI treatment with miR-145 protected the heart through the induction of cardiomyocyte autophagy by targeting fibroblast growth factor receptor substrate 2.
Insights
MicroRNA-145 (miR-145) shows cardioprotective effects after myocardial infarction (MI) by promoting cardiomyocyte autophagy. This treatment reduced infarct size and improved cardiac function in a rabbit MI model.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Biochemistry
Background:
- Myocardial infarction (MI) remains a leading cause of mortality, necessitating novel therapeutic strategies.
- MicroRNAs (miRNAs) are emerging as critical regulators of cardiac function and disease.
- The role of microRNA-145 (miR-145) in post-MI cardiac protection is not fully elucidated.
Purpose of the Study:
- To investigate the cardioprotective potential of miR-145 in a rabbit model of myocardial infarction (MI).
- To elucidate the underlying molecular mechanisms, including autophagy and target gene regulation, of miR-145's effects.
- To assess miR-145's impact on cardiac function, remodeling, and cell viability in vitro.
Main Methods:
- A rabbit model of MI was established via coronary artery occlusion and reperfusion.
- Intravenous administration of miR-145 encapsulated in liposomes was performed post-MI.
- H9c2 rat cardiomyoblasts were used for in vitro studies, including transfection with miR-145 and antagomir-145.
- Cardiac function, infarct size, autophagy markers (LC3B, p62), Akt phosphorylation, and target gene expression were assessed.
Main Results:
- miR-145 treatment significantly reduced infarct size and improved cardiac function and remodeling at 2 days and 2 weeks post-MI.
- miR-145 promoted cardiomyocyte autophagy, evidenced by increased LC3B-II/LC3B-I ratio and decreased p62 levels.
- miR-145 activated Akt signaling and inhibited H9c2 cell growth, with these effects being reversed by chloroquine and antagomir-145.
- Fibroblast growth factor receptor substrate 2 (FGFRSS2) mRNA was identified as a direct target of miR-145.
Conclusions:
- Post-MI administration of miR-145 confers significant cardioprotection in a rabbit model.
- miR-145 exerts its protective effects by inducing cardiomyocyte autophagy via targeting FGFRSS2.
- These findings highlight miR-145 as a potential therapeutic agent for treating myocardial infarction.
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