Nuclear miR-665 aggravates heart failure via suppressing phosphatase and tensin homolog transcription.

Abstract

Although numerous miRNAs have been discovered, their functions in the different subcellular organelles have remained obscure. In this study, we found that miR-665 was enriched in the nucleus of cardiomyocytes, and then investigated the underlying role of nuclear miR-665 in heart failure. RNA fluorescence in situ hybridization assays in human heart tissue sections and primary cardiomyocytes showed that miR-665 was localized in the nucleus of cardiomyocytes. Increased expression of nuclear miR-665 was observed not only in the cardiomyocytes isolated from the heart of mice treated in vivo by transverse aortic constriction (TAC), but also in phenylephrine (PE)-treated cultured cardiomyocytes in vitro. To further explore the role of miR-665 in heart failure, a type 9 recombinant adeno-associated virus (rAAV) system was employed to manipulate the expression of miR-665 in mice. Overexpression of miR-665 aggravated TAC-induced cardiac dysfunction, while down-expression of miR-665 showed opposite effects. Bioinformatic prediction and biological validation confirmed that the PTEN (phosphatase and tensin homolog) gene was one of the targets of miR-665 in the nucleus. Furthermore, restoring PTEN expression significantly eliminated the destructive effects of miR-665 over-expression in TAC-induced cardiac dysfunction. Our data showed that nuclear miR-665 aggravates heart failure via inhibiting PTEN expression, which provided a therapeutic approach for heart failure.