Department of Paediatrics, The 306th Hospital of PLA, Beijing, 100101, China.
Department of Pediatric Intensive Care Unit, BaYi Children's Hospital of PLA Army General Hospital, Beijing, 100700, China.
Biomed Pharmacother. 2018 Oct;106:692-698. doi: 10.1016/j.biopha.2018.07.017. Epub 2018 Jul 11.
This study investigated the impact of SO on rats with hypoxic pulmonary vascular structural remodeling and its possible mechanisms.
Pulmonary vascular morphological change was examined by HE staining. RNA-based high-throughput sequencing (RNA-seq) was performed to detect differential expression of mRNAs in Normal and Hypoxia-induced Pulmonary hypertension (HPH) rats. The Real-time quantitative RT-PCR (q RT-PCR) was used for validation of wnt7b, sfrp2, cacna1f, DKK1, CaSR and vimentin mRNA expression levels. Protein levels of CaSR, Vimentin, Caspase3, E-cadherin and P-Akt1/2/3 were detected by Western blot and immunohistochemistry.
This study showed that SO significantly attenuated the interstitial thickening and prominent media hypertrophy of pulmonary arteries. SO downregulated p-Akt1/2/3 protein level and upregulated E-cadherin protein level in lung tissues, which inhibited the proliferation and epithelial-to-mesenchymal transition (EMT) in HPH rats. RNA-seq and PCR validation results showed that levels of Wnt7b, Sfrp2 and Cacna1f mRNAs decreased and Dkk1 mRNA level increased obviously in HPH rats. Moreover, SO attenuated the mRNA and protein level of CaSR, which was activated in HPH rats and resulted in the proliferation of PASMCs. Besides, the mRNA and protein expression of vimentin in PASMCs significantly reduced after SO treatment.
Together, these findings indicate that SO could attenuate hypoxia-induced pulmonary arteriolar remodeling and may suppress the proliferation and migration of PASMCs at least in part through the Dkk1/Wnt signaling pathway.
本研究旨在探讨 SO 对低氧性肺血管结构重构大鼠的影响及其可能机制。
通过 HE 染色观察肺血管形态变化。采用 RNA 高通量测序（RNA-seq）检测正常和缺氧诱导性肺动脉高压（HPH）大鼠中 mRNAs 的差异表达。实时定量 RT-PCR（q RT-PCR）验证 wnt7b、sfrp2、cacna1f、DKK1、CaSR 和 vimentin mRNA 表达水平。Western blot 和免疫组化检测 CaSR、Vimentin、Caspase3、E-cadherin 和 P-Akt1/2/3 蛋白水平。
本研究表明，SO 可显著减轻肺血管间质增厚和中膜肥厚。SO 下调肺组织中 p-Akt1/2/3 蛋白水平，上调 E-cadherin 蛋白水平，抑制 HPH 大鼠增殖和上皮间质转化（EMT）。RNA-seq 和 PCR 验证结果显示，HPH 大鼠中 Wnt7b、Sfrp2 和 Cacna1f mRNA 水平降低，DKK1 mRNA 水平明显升高。此外，SO 可减轻 HPH 大鼠中 CaSR 的 mRNA 和蛋白水平，从而导致 PASMCs 增殖。此外，SO 处理后 PASMCs 中 vimentin 的 mRNA 和蛋白表达明显减少。
综上所述，这些发现表明 SO 可减轻低氧诱导的肺小动脉重构，并可能通过 DKK1/Wnt 信号通路抑制 PASMCs 的增殖和迁移。
