The aberrant proliferation of pulmonary artery smooth muscle (PASMCs) cells is a defining characteristic of pulmonary arterial hypertension (PAH) and leads to increased vascular resistance, elevated pulmonary pressure, and right heart failure. The sphingosine kinase 1 (SPHK1)/sphingosine-1 phosphate/sphingosine-1 phosphate receptor 2 pathway promotes vascular remodeling and induces PAH. The aim of this study was to identify genes and cellular processes that are modulated by over-expression of SPHK1 in human PASMCs (hPASMCs). RNA was purified and submitted for RNA sequencing to identify differentially expressed genes. Using a corrected p-value threshold of <0.05, there were 294 genes significantly up-regulated while 179 were significantly down-regulated. Predicted effects of these differentially expressed genes were evaluated using the freeware tool Enrichr to assess general gene set over-representation (enrichment) and ingenuity pathway analysis (IPA™) for upstream regulator predictions. We found a strong change in genes that regulated the cellular immune response. IL6, STAT1, and PARP9 were elevated in response to SPHK1 over-expression in hPASMCs. The gene set enrichment mapped to a few immune-modulatory signaling networks, including IFNG. Furthermore, PARP9 and STAT1 protein were elevated in primary hPASMCs isolated from PAH patients. In conclusion, these data suggest a role of Sphk1 regulates pulmonary vascular immune response in PAH.

肺动脉平滑肌 (PASMC) 细胞的异常增殖是肺动脉高压 (PAH) 的定义特征，并导致血管阻力增加、肺压升高和右心衰竭。鞘氨醇激酶 1 (SPHK1)/sphingosine-1 phosphate/sphingosine-1 磷酸受体 2 通路促进血管重塑并诱导 PAH。本研究的目的是鉴定受人类 PASMC (hPASMC) 中 SPHK1 过表达调节的基因和细胞过程。RNA被纯化并提交用于RNA测序以鉴定差异表达的基因。使用 <0.05 的校正 p 值阈值，有 294 个基因显着上调，而 179 个基因显着下调。使用免费软件工具 Enrichr 评估这些差异表达基因的预测效果，以评估上游调节因子预测的一般基因集过度表达（富集）和独创性途径分析 (IPA™)。我们发现调节细胞免疫反应的基因发生了强烈变化。响应于 hPASMC 中 SPHK1 过表达，IL6、STAT1 和 PARP9 升高。基因集富集映射到一些免疫调节信号网络，包括 IFNG。此外，从 PAH 患者分离的原发性 hPASMC 中 PARP9 和 STAT1 蛋白升高。总之，这些数据表明 Sphk1 在 PAH 中调节肺血管免疫反应的作用。我们发现调节细胞免疫反应的基因发生了强烈变化。响应于 hPASMC 中 SPHK1 过表达，IL6、STAT1 和 PARP9 升高。基因集富集映射到一些免疫调节信号网络，包括 IFNG。此外，从 PAH 患者分离的原发性 hPASMC 中 PARP9 和 STAT1 蛋白升高。总之，这些数据表明 Sphk1 在 PAH 中调节肺血管免疫反应的作用。我们发现调节细胞免疫反应的基因发生了强烈变化。响应于 hPASMC 中 SPHK1 过表达，IL6、STAT1 和 PARP9 升高。基因集富集映射到一些免疫调节信号网络，包括 IFNG。此外，从 PAH 患者分离的原发性 hPASMC 中 PARP9 和 STAT1 蛋白升高。总之，这些数据表明 Sphk1 在 PAH 中调节肺血管免疫反应的作用。