MiR‑449a‑5p suppresses CDK6 expression to inhibit cardiomyocyte proliferation.

Abstract

Induction of cardiomyocyte (CM) proliferation is a promising approach for cardiac regeneration following myocardial injury. MicroRNAs (miRs) have been reported to regulate CM proliferation. In particular, miR-449a-5p has been identified to be associated with CM proliferation in previous high throughput functional screening data. However, whether miR-449a-5p regulates CM proliferation has not been thoroughly investigated. This study aimed to explore whether miR-449a-5p modulates CM proliferation and to identify the molecular mechanism via which miR-449a-5p regulates CM proliferation. The current study demonstrated that miR-449a-5p expression levels were significantly increased during heart development. Furthermore, the results suggested that miR-449a-5p mimic inhibited CM proliferation in vitro as determined via immunofluorescence for ki67 and histone H3 phosphorylated at serine 10 (pH3), as well as the numbers of CMs. However, miR-449a-5p knockdown promoted CM proliferation. CDK6 was identified as a direct target gene of miR-449a-5p, and CDK6 mRNA and protein expression was suppressed by miR-449a-5p. Moreover, CDK6 gain-of-function increased CM proliferation. Overexpression of CDK6 also blocked the inhibitory effect of miR-449a-5p on CM proliferation, indicating that CDK6 was a functional target of miR-449a-5p in CM proliferation. In conclusion, miR-449a-5p inhibited CM proliferation by targeting CDK6, which provides a potential molecular target for preventing myocardial injury.