AUTHOR=Wang Wei , Jiang Zhenhong , Zhang Dandan , Fu Linghua , Wan Rong , Hong Kui 

TITLE=Comparative Transcriptional Analysis of Pulmonary Arterial Hypertension Associated With Three Different Diseases

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=9

YEAR=2021

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.672159

DOI=10.3389/fcell.2021.672159

ISSN=2296-634X

ABSTRACT=<p>Pulmonary arterial hypertension (PAH) is a severe cardiovascular disorder with high mortality. Multiple clinical diseases can induce PAH, but the underlying molecular mechanisms shared in PAHs associated with different diseases remain unclear. The aim of this study is to explore the key candidate genes and pathways in PAH associated with congenital heart disease (CHD-PAH), PAH associated with connective tissue disease (CTD-PAH), and idiopathic PAH (IPAH). We performed differential expression analysis based on a public microarray dataset GSE113439 and identified 1,442 differentially expressed genes, of which 80.3% were upregulated. Subsequently, both pathway enrichment analysis and protein–protein interaction network analysis revealed that the “Cell cycle” and “DNA damage” processes were significantly enriched in PAH. The expression of seven upregulated candidate genes (<italic>EIF2AK2</italic>, <italic>TOPBP1</italic>, <italic>CDC5L</italic>, <italic>DHX15</italic>, and <italic>CUL1</italic>–<italic>3</italic>) and three downregulated candidate genes (<italic>DLL4</italic>, <italic>EGFL7</italic>, and <italic>ACE</italic>) were validated by qRT-PCR. Furthermore, cell cycle-related genes <italic>Cul1</italic> and <italic>Cul2</italic> were identified in pulmonary arterial endothelial cells (PAECs) <italic>in vitro.</italic> The result revealed an increased expression of <italic>Cul2</italic> in PAECs after hypoxic treatment. Silencing <italic>Cul2</italic> could inhibit overproliferation and migration of PAECs in hypoxia. Taken together, according to bioinformatic analyses, our work revealed that “Cell cycle” and “DNA damage” process-related genes and pathways were significantly dysregulated expressed in PAHs associated with three different diseases. This commonality in molecular discovery might broaden the genetic perspective and understanding of PAH. Besides, silencing <italic>Cul2</italic> showed a protective effect in PAECs in hypoxia. The results may provide new treatment targets in multiple diseases induced by PAH.</p>