Potential Key Proteins, Molecular Networks, and Pathways in Perinatal Hypoxia

Perinatal hypoxia is a common risk factor for CNS development. Using bioinformatics databases, a list of 129 genes involved in perinatal hypoxia was selected from the literature and analyzed with respect to proteins important for biological processes influencing the brain development. Functional enrichment analysis using the DAVID database was performed to identify relevant Gene Ontology (GO) biological processes like response to hypoxia, inflammatory response, positive and negative regulation of apoptosis, and positive and negative regulation of cell proliferation. The selected GO processes contain 17-30 proteins and show an enrichment of 6.3-14.3-fold. The STRING protein-protein interaction network and the Cytoscape data analyzer were used to identify interacting proteins playing a significant role in these processes. The two top protein pairs referring to the proteins with highest degrees and the corresponding proteins connected by high score edges exert opposite or regulatory functions and are essential for the balance between damaging, repairing, protective, or epigenetic processes. The GO response to hypoxia is characterized by the high score protein-protein interaction pairs CASP3/FAS promoting apoptosis and by the protective acting BDNF/MECP2 protein pair. Core components of the GO processes positive and negative regulation of apoptosis are the proteins CASP3/FAS/AKT/eNOS/RPS6KB1 involved in several signal pathways. The GO processes cell proliferation are characterized by the high-score protein-protein interaction pairs MYC/ MAPK1, JUN/MAPK1, IL6/IL1B, and JUN/HDAC1. The study provides new insights into the pathophysiology of perinatal hypoxia and is of importance for future investigations, diagnostics, and therapy of perinatal hypoxia.