Abstract
Pulmonary artery adventitial fibroblasts, the most abundant cellular constituent of adventitia, are often the first to be activated and reprogrammed to then influence the tone and structure of the vessel wall in pulmonary arterial hypertension (PAH). Our previous study found that interruption of CD40 ligand (CD40L)-CD40 signaling improves the efficacy of transplanted endothelial progenitor cells in monocrotaline induced-PAH. However, whether CD40L-CD40 signaling is involved in the activation of adventitial fibroblasts in PAH and whether Drosophila behavior human splicing (DBHS) protein family members have any roles during adventitial fibroblasts activation are completely unclear. Here, we show that soluble CD40L (sCD40L) stimulation progressively increases pro-inflammatory activity, proliferation, and migration of pulmonary adventitial fibroblasts. Besides, sCD40L stimulation decreases splicing factor proline- and glutamine-rich protein (SFPQ) protein (one member of DBHS protein family) expression, while SFPQ overexpression suppresses sCD40L stimulation-induced proliferation and migration of pulmonary adventitial fibroblasts by repressing CD40 transcription. Moreover, ChIP assays found that sCD40L stimulation promotes histone H3 tri-methylation at lysine 4 (H3K4me3), H3K36me3, and H3K27 acetylation (H3K27ac) modifications on CD40 promoter region in pulmonary adventitial fibroblasts, while SFPQ overexpression decreases H3K36me3 modification and increases H3K36ac on CD40 promoter region by interacting with histone deacetylase-1 (HDAC1) to inhibit CD40 transcription. This in-depth study shows that CD40L-CD40 signaling promotes activation of pulmonary adventitial fibroblasts by increasing proliferation, migration, and pro-inflammatory activity of adventitial fibroblasts, and SFPQ could inhibit CD40 transcription though switching H3K36me3 to H3K36ac modifications on its promoter by interacting with HDAC1. This study, first, uncovers the roles of SFPQ on CD40L-CD40 signaling-mediated activation of pulmonary adventitial fibroblasts.