In male pulmonary artery endothelial cells, hypoxia decreased ADAR1 protein and mRNA expression by 40% and 30% respectively (p=0.0003; 0.0001), which was restored with ESR2 silencing.
ERβ negatively regulates ADAR1 expression in male PAECs, suggesting a link between hypoxia-induced ERβ upregulation and post-transcriptional changes in pulmonary hypertension.
p-value: p=0.0003
Abstract Rationale Pulmonary hypertension (PH) is a heterogeneous and sexually dimorphic disease that remains a leading contributor of cardiovascular morbidity and mortality. Post-transcriptional dysregulation in pulmonary artery endothelial cells (PAECs) contributes to vascular remodeling across PH subtypes, and RNA-editing deficiency has been found in the endothelium of human PH lungs. Downregulation of the RNA editing enzyme adenosine deaminase acting on RNA 1 (ADAR1, gene code ADAR) is observed in hypoxic PH-like PAECs when estrogen receptor β (ERβ) is upregulated. Thus, we hypothesized that increased ERβ activity represses ADAR1 expression in hypoxic PH-like PAECs. Methods Lung ECs were isolated from wild-type (WT) or ERα mutant (ERαmut) rats. Human male PAECs were utilized in vitro studies. PAECs were exposed to hypoxia (1% O2, 24h). To modulate ERβ activity, an ERβ-agonist, Diarylpropionitrile (100nM DPN, 24h), or siRNA directed against ESR2 (the gene encoding ERβ; 10nM, 48h) were used. ADAR1 (ADAR) or ERβ (ESR2) expression was determined by immunoblotting or RT-qPCR. P 0.05 was considered significant. Results ADAR1 levels were not altered between WT and ERαmut rat lung ECs. In male PAECs, hypoxia decreased ADAR1 protein and mRNA expression by 40% and 30% respectively (p = 0.0003; 0.0001). Hypoxia increased ERβ expression by 33% in PAECs (p 0.05; Frump et al., AJRCMB 2018). DPN treatment reduced ADAR1 protein by 30% in PAECs. Conversely, ESR2 siRNA (90% knockdown on RT-qPCR) significantly upregulated ADAR1 protein levels, but was not reversible with DPN exposure. ADAR1 downregulation in hypoxic PAECs was restored with ESR2 silencing. Conclusions ERβ negatively regulates ADAR1 expression in male PAECs. This molecular relationship provides insight into how hypoxia-induced ERβ upregulation may contribute to the post-transcriptional changes in PAECs. Clinically, this work highlights a potential intersection between hormonal signaling and RNA-editing pathways that may inform new therapeutic directions in PH. This abstract is funded by: R00HL161320
Jost et al. (2026) studied Pulmonary hypertension. Hypoxia, Diarylpropionitrile (DPN), or ESR2 siRNA was evaluated on ADAR1 protein and mRNA expression (p=0.0003). In male pulmonary artery endothelial cells, hypoxia decreased ADAR1 protein and mRNA expression by 40% and 30% respectively (p=0.0003; 0.0001), which was restored with ESR2 silencing.