MicroRNA deregulation in right ventricular outflow tract myocardium in nonsyndromic tetralogy of fallot

摘要

Background: Tetralogy of Fallot (TOF) is 1 of the most common heart defects in children, and the underlying mechanisms remain largely elusive. MicroRNAs (miRNAs) are a class of regulators of gene expression and are increasingly recognized for their roles in heart development. Methods: To identify miRNAs abnormally expressed in TOF, microarrays were used to analyze the miRNA expression profiles of 5 samples of myectomy tissues from right ventricular outflow tract (RVOT) obstruction of infants with nonsyndromic TOF and 3 age-matched normal RVOT tissues. Results: In total, 41 candidate miRNAs were identified. To further validate the microarray results, the 41 miRNAs were detected using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in a larger independent population of tissue samples, including 21 from patients with TOF and 6 from normal controls; it was found that 18 miRNAs were expressed at significantly different levels. Bioinformatic analysis revealed that these miRNAs targeted a network of genes involved in heart development and human congenital heart diseases. Further invitro studies indicated that upregulation of miR-424/424* promoted proliferation and inhibited migration of primary embryonic mouse cardiomyocytes, whereas miR-222 promoted cardiomyocyte proliferation and reduced the cardiomyogenic differentiation of P19 cells. The 3'UTR (3' untranslated region) luciferase assay revealed that miR-424/424* suppressed the expression of HAS2 and NF1, and their mRNAs were underexpressed in the RVOT myocardial tissues of TOF. Conclusions: Eighteen miRNAs were identified as being deregulated in RVOT myocardial tissues from infants with nonsyndromic TOF, and invitro experiments indicated that miR-424/424* and miR-222 are involved in cardiomyocyte proliferation and migration and the cardiomyogenic differentiation of P19 cells.