Abstract 15518: Overexpression of MicroRNA-210 Induces Cardiomyocyte Proliferation Through Inhibition of APC
Background: MicroRNAs (miRs) transcriptionally regulate various cell functions including survival, differentiation and proliferation. Here, we report that transgenic overexpression of miR-210 in mice promoted cardiomyocyte (CM) proliferation by the inhibition of Adenomatous polyposis coli (APC), a cell cycle inhibitor.
Methods and Results: miR-210 transgenic mice (miR-210 TG) were generated at the University of Cincinnati transgenic core using C57BL/6 mouse strain. Myocardial infarction was created by LAD ligation on 12 weeks old miR-210 TG and wild type (NTG) mice following which EDU was administrated at a dose of 500μg in 100μl/ IP injection on alternate days up to day 12. For long term studies 4 weeks after ligation echocardiography was performed, animals were sacrificed and the heart sections were analyzed for apoptosis and CMs proliferation. For short term studies animals were sacrificed 7 days after LAD ligation. TUNEL assay at day 7 showed significantly lower percentage of apoptotic CMs in miR-210 mice compared to that of controls (3.12±0.6% vs 6.13±0.8%, p<0.05). At day 7 miR-210 TG group showed a higher number of EDU+ CMs but were not significant when compared to that of controls. However, at week 4 after infarction, significantly higher percentage of EDU+ CMs were observed in miR-210 TG group compared to that of NTG (1.11±0.05% vs 0.47±0.01%, p<0.05). Echocardiography performed prior to euthanasia showed preserved cardiac function in mir-210 TG as compared to NTG as indicated by LVEF (45.2±1.06 vs 38.9±1 p<0.001) and LVFS (18.3±1 vs 15±1. Furthermore, mesenchymal stem cells (MSCs) from miR-210 mice displayed significantly lower level of APC protein compared to that of wild type mouse MSCs. Further studies to identify the in vitro proliferative potential of miR-210 were carried out using 7 day old neonatal rat CMs, miR-210 transfection showed a significant increase in proliferation in miR-210 TG group when compared to control (38.67 ± 3.37 vs 6.7 ± 3.24). Computational prediction and Luciferase assay indicated a direct relationship between miR-210 and APC ( 2 fold reduction in luciferase activity).
Conclusions: Transgenic overexpression of miR-210 in mice induces CM proliferation at least in part, through down regulation of APC.
Author Disclosures: V.K. Lai: None. R. Pandey: None. S. Durrani: None. G. Ma: None. S. Jiang: None. R.P. Ahmed: None.
- © 2014 by American Heart Association, Inc.