Abstract
ObjectivePatent ductus arteriosus (PDA) is a congenital heart defect with an unclear etiology that occurs commonly among newborns. Adequately understanding the molecular pathogenesis of PDA can contribute to improved treatment and prevention. Plasma proteins may provide evidence to explore the molecular mechanisms of abnormal cardiac development.MethodsIsobaric tags for relative and absolute quantitation (iTRAQ) proteomics technology was used to measure different plasma proteins in PDA patients (n = 4) and controls (n = 4). The candidate protein was validated by ELISA and Western blot (WB) assays in a larger sample. Validation of the location and expression of this protein was performed in mouse heart sections.ResultsThere were three downregulated proteins and eight upregulated proteins identified in the iTRAQ proteomics data. Among these, protein disulfide-isomerase A6 (PDIA6) was further analyzed for validation. The plasma PDIA6 concentrations (3.2 ± 0.7 ng/ml) in PDA patients were significantly lower than those in normal controls (5.8 ± 1.2 ng/ml). In addition, a WB assay also supported these results. PDIA6 was widely expressed in mouse heart outflow tract on embryonic day 14.5.ConclusionPlasma proteomics profiles suggested novel candidate molecular markers for PDA. The findings may allow development of a new strategy to investigate the mechanism and etiology of PDA.
Highlights
Patent ductus arteriosus (PDA) is a condition in which the ductus arteriosus fails to close after birth; PDA is the second most common congenital heart disease (CHD) [1]
No significant differences were found between the PDA and control groups in Isobaric tags for relative and absolute quantitation (iTRAQ) proteomics and Enzyme-linked immunosorbent assay (ELISA) analyses
We discovered that circulating protein disulfide-isomerase A6 (PDIA6) was downregulated in PDA patients compared with in healthy controls
Summary
Patent ductus arteriosus (PDA) is a condition in which the ductus arteriosus fails to close after birth; PDA is the second most common congenital heart disease (CHD) [1]. The fetal patency of the ductus arteriosus is controlled by a variety of factors, the most crucial factors are low fetal oxygen tension and cyclooxygenase-mediated metabolites of arachidonic acid (mainly prostaglandin E2 [PGE2] and prostacyclin [PGI2]) [3, 4]. Circulating PGE2 and PGI2 in the fetus cause ductus arteriosus vasodilatation by interacting with the ductal prostaglandin receptor [5]. The sudden increase in oxygen tension inhibits the voltage-dependent potassium channel in the cardiac smooth muscle, which leads to an influx of calcium and ductal contraction [6]. PGE2 and PGI2 levels decline due to metabolic lung function and elimination of their placental origin. The medial smooth muscle fibers in the heart lead to thickening of the wall, obliteration of the lumen, and shortening of the ductus arteriosus. Functional closure usually occurs within 24 to 48 h of term
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