Abstract
Rationale: Embryonic heart is characteristic of rapidly dividing cardiomyocytes that give rise to sufficient numbers required to build a working myocardium. In contrast, cardiomyocytes retain some proliferative capacity in the neonates but lose most of it in adulthood. Embryonic stem cell cycle (ESCC) miRs are a class of microRNAs regulating the unique cell cycle of ESCs and their characteristic pluripotency. Nevertheless, expression of miR-294, a member of the ESCC miRs is lost during developmental transitions from the ESCs to mature cells. Effect of miR-294 to induce cardiac proliferation and heart function has not been previously studied. Objective: To determine whether miR-294 drives cardiomyocyte cell cycle reentry leading to augmentation of cardiac function after myocardial infarction. Methods and Results: miR expression analysis was carried out in the heart during development to determine levels of miR-294. Elevated level of miR-294 was observed in the prenatal heart confirmed by qRT-PCR. In contrast, miR-294 expression is lost in the neonates and adult mice. To further assess the effect of miR-294, neonatal ventricular cardiomyocytes (NRVMs) were treated with miR-294 mimic to determine the effect on proliferation and cell cycle. Elevated mRNA levels of cyclins A2 and E1 together with CDK2 was observed in NRVMs treated with 25nM mimic for miR-294. Increased expression of p-histone 3, PCNA (S-phase), Aurora B kinase (G2/M) and Ki67 was confirmed by immunocytochemistry in NRVMs after miR-294 treatment compared to control cells. Intramyocardial administration of miR-294 was carried out in mice at the time of myocardial infarction to determine whether miR-294 delivery increases cardiomyocyte proliferation and survival in response to injury. Enhance cardiac function was observed in mice receiving miR-294 3 weeks after myocardial infarction. Concurrently, increase myocyte proliferation was observed in the heart after miR-294 treatment as analyzed by BrdU uptake, PCNA and Aurora B expression by immunostaining. Conclusion: Ectopic expression of miR-294 recapitulates embryonic signaling and enhances cardiomyocyte ability to proliferate and reenter the cell cycle leading to augmented cardiac function in mice after myocardial infarction.
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