Gene expression profile in persistent pulmonary hypertension of newborn, preliminary report

María de Lourdes Lemus-Varela, Mario Eduardo Flores-Soto, Veronica Chaparro-Huerta, Blanca Miriam Torres-Mendoza, Sergio G. Golombek, Carlos Beas-Zárate

Abstract


Background: Persistent pulmonary hypertension of the newborn (PPHN) is a serious condition with high morbidity and mortality. The therapeutic approach, even today, represents a major challenge. There is considerable interest in the understanding of the signaling pathways that regulate vasoconstriction and pulmonary vascular remodeling.

Objective: We set out to identify the expression of genes S100A9 and solutes transporter, as well as their participation in the physiopathological events of PPHN.

Design and methods: This is a cross-sectional study that focuses mainly on up- and down-regulated genes involved in endothelial metabolism, hypoxia transporters, ionic and nucleotides metabolism. The total RNA was obtained from blood samples of healthy full-term newborns (negative controls) and patients with PPHN. The preparation of samples for microarray analysis was as follows: control samples were stained with fluorescent nucleotides dUTP-Cy3 and pathological samples with dUTP-Cy5; samples were co-hybridized, a microarray analysis was performed using an Array Scanner Packard. Additionally, reverse transcriptase polymerase chain reaction (RT-PCR) for the genes S100A9 and solutes transporter was done. Comparative and descriptive analyses were done using t-test for independent variables, considering a p < 0.05 as significant. The elements with a z-score of more than 2 standard deviations are genes likely to be differentially expressed.

Results: From the total (10,000) genes analyzed, 364 (3.64%) were differentially regulated in their expression; those that registered an up-regulation were 1.13%, while 2.51% were down-regulated. S100 proteins type A9 and A12 were the most over-expressed, as well as Rho family GTPase 3. Down-regulation in the hypoxia-inducible factor 1 (HIF-1) and HIF-1 alpha subunit inhibitor was found. S100A9 and RSC1A1 had increased mRNA expression under PPHN conditions compared to healthy newborn infants.

Conclusions: The up-regulation from both genes could explain, in part, the vasoreactivity and vascular remodeling characteristic of PPHN. A deeper understanding of the pathophysiology of PPHN could have a positive impact on the development of specific therapies.


Keywords


persistent pulmonary hypertension of newborn; gene S100A9; solutes transporter; RT-PCR

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