Intimate intertwining of the pathogenesis of hypoxia and systemic sclerosis: A transcriptome integration analysis

Abstract

ObjectivesSystemic sclerosis (SSc) is an autoimmune disease caused by various pathogenic factors, including hypoxia. Hypoxia stimulates the production of the extracellular matrix to promote fibrosis. However, the integrated function and the underlying mechanism of hypoxia in SSc are unclear.MethodsIn the present study, we used Agilent SurePrint G3 Human Gene Expression v3 for the transcriptional sequencing of fibroblasts with and without hypoxia to detect differentially expressed genes (DEGs) in hypoxia. We analyzed the results with the transcriptome data of SSc lesions (GSE95065) to select the co-DEGs. Then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed on the basis of the co-DEGs using the R package ClusterProfiler, which showed that hypoxia and cross talk of hypoxia with other pathogenic factors are involved in the pathogenesis of SSc. Furthermore, we constructed a protein–protein interaction (PPI) network of co-DEGs and screened two significant functional expression modules.ResultsWe identified nine hub genes (ALDH1A1, EGF, NOX4, LYN, DNTT, PTGS2, TKT, ACAA2, and ALDH3A1). These genes affect the pentose phosphate pathway, oxidative stress, and lipolysis.ConclusionOur study provides insights into the mechanisms underlying the effects of hypoxia on SSc pathogenesis, which will help to better understand SSc pathogenesis and develop new therapeutic strategies for SSc.

Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: From Bedside to Bench and Back Again

“…HIF-1α/VEGF signaling pathway plays an important role in mediating the effect of hypoxia-induced EndMT, in the skin microvascular remodeling of SSc [159]. By analyzing differential transcriptomic data from fibroblasts with and without hypoxia treatment, He et al identified nine hypoxia-associated hub genes affecting the pentose phosphate pathway, oxidative stress, and lipolysis, which implicated roles of hypoxiamediated-non-fibrosis mechanisms on SSc pathogenesis [160]. In SSc-PAH patients, a cohort study found that the single nucleotide polymorphism of HIF1A gene (rs12434438 SNP) may be associated with severe PAH among SSc patients [161].…”