MicroRNA-210-mediated proliferation, survival, and angiogenesis promote cardiac repair post myocardial infarction in rodents
Mohammed Arif, Raghav Pandey, Perwez Alam, Shujia Jiang, Sakthivel Sadayappan, Arghya Paul, Rafeeq P.H. AhmedJournal of Molecular Medicine2017
An innovative approach for cardiac regeneration following injury is to induce endogenous cardiomyocyte (CM)cell cycle re-entry. In the present study, CMs from adult rat hearts were isolated and transfected with cel-miR-67 (control) and rno- miR-210. A significant increase in CM proliferation and mono-nucleation were observed in miR-210 group, in addi- tion to a reduction in CM size, multi-nucleation, and cell death. When compared to control, β-catenin and Bcl-2 were upregulated while APC (adenomatous polyposis coli), p16, and caspase-3 were downregulated in miR-210 group. In silico analysis predicted cell cycle inhibitor, APC, as a direct target of miR-210 in rodents.Moreover, compared to control, a significant increase in CM survival and proliferation were ob- served with siRNA-mediated inhibition of APC. Furthermore, miR-210 overexpressing C57BL/6 mice (210-TG) were used for short-term ischemia/reperfusion study, revealing smaller cell size, increasedmono-nucleation, decreased multi-nucleation, and increased CMproliferation in 210-TG hearts in contrast to wild- type (NTG). Likewise,myocardial infarction (MI) was created in adult mice, echocardiography was performed, and the heart were harvested forimmunohistochemistry andmolecular studies. Compared to NTG, 210-TG hearts showed a significant increase in CM proliferation, reduced apoptosis, upregulated angiogene- sis, reduced infarct size, and overall improvement in cardiac function following MI. β-catenin, Bcl-2, and VEGF (vascular endothelial growth factor) were upregulated while APC, p16, and caspase-3 were downregulated in 210-TG hearts. Overall, constitutive overexpression of miR-210 rescues heart function following cardiac injury in adultmice via promoting CM prolif- eration, cell survival, and angiogenesis.