Persistent pulmonary hypertension of the newborn (PPHN) is a rapidly progressive and potentially fatal vasculopathy stemming from a failure of the pulmonary vascular resistance (PVR) to drop at or shortly after birth. Recent studies suggest that microRNAs (miRNAs) are dysregulated in adult and experimental pulmonary hypertension.
The goal of this study was to identify potential miRNAs involved in the pathogenesis of PPHN.
In a case-control study, expression profiles of miRNAs were investigated in de-identified formalin fixed paraffin embedded (FFPE) postmortem lung specimens from 12 infants with PPHN and 12 infants who died of other causes.
We have completed microarray analysis of microRNA expression in archived (FFPE) samples from 12 PPHN and 12 control subjects. MicroRNAs that were detected in at least 8 of 12 samples for either the PPHN or control groups were selected reducing the total set from 2570 to 1202. Statistical analysis was performed with a moderated t-test and correction of p-values with the Storey bootstrap method. Stringent criteria were used to select 12 microRNAs significantly different between the two groups: 1) q-values <=0.05 (5% FDR); and 2) minimum 1.5-fold change between PPHN and control. We then focused on three of the differentially expressed microRNAs that had predicted target genes associated with the disease etiology: miR-379-5p, miR-7977, and miR-455-3p. Among the relevant predicted target genes of these miRs are prostaglandin E synthase, endothelin and cardiac t-box factor TBX20. The latter has been associated with cardiac defects and pulmonary hypertension. We used quantitative RT-PCR to confirm that these three microRNAs were repressed (lower expression) in the PPHN cases.
This is the first study to identify miRNAs associated with PPHN in archived postmortem lung specimens. These may contribute to the pathogenesis of PPHN and may provide potential novel therapeutic approaches for the treatment of PPHN.