Molecular substrates of covid-19 and pulmonary arterial hypertension identified through signalling network construction

Abstract

Pulmonary arterial hypertension (PAH) is a serious condition that occurs when high blood pressure builds up in pulmonary arteries, affecting blood circulation from the heart to the lungs, which can ultimately lead to heart failure and death. COVID-19 pandemic exhibits genuine challenges for PAH patients. Therefore, novel strategies for the management of PAH patients with COVID-19 are needed. However, molecular mechanisms underlying the crosstalk between two diseases have not been fully understood. In the current study, we elucidated similarities and differences in the re-organization of transcriptional response in the presence of PAH and COVID-19 and identify molecular substrates of both diseases by constructing signalling networks. For this purpose, gene expression data obtained from lung tissues of PAH and COVID-19 patients were comparatively analysed and differentially expressed genes (DEGs) were identified. Then, reporter molecules (i.e., metabolites, transcription factors (TFs) and microRNAs (miRNAs)) were discovered by integrating transcriptome data with human metabolic and regulatory networks. Consequently, signalling networks were constructed by merging the interactions between regulatory molecules and DEGs. COVID-19 network contained 2546 interactions between 558 DEGs, 89 metabolites, 6 TFs and 128 miRNAs, whereas PAH network contained 29266 interactions between 3955 DEGs, 112 metabolites, 22 TFs and 356 miRNAs. A total of 207 reporter molecule-DEG interactions were found to be common in both diseases. Functional enrichment analysis of these reporter molecules was performed via interacting DEGs, and revealed significant alterations in cardiac muscle contraction, oxidative phosphorylation, non-alcoholic fatty liver disease, diabetic cardiomyopathy, thermogenesis, and several cardiovascular, infectious, and neurodegenerative disease pathways. Moreover, gene-based drug repositioning analysis revealed candidate drugs including cardiac glycosides, insulin sensitizers, and drugs with antifibrotic, anti-inflammatory, and antiproliferative effects, for consideration in future clinical drug development.