Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Changsha, 410078, China.
Exp Cell Res. 2024 Oct 1;442(2):114254. doi: 10.1016/j.yexcr.2024.114254. Epub 2024 Sep 12.
Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder characterized by pulmonary vascular remodeling (PVR), primarily due to the excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). This study aimed to investigate the role and molecular mechanism of SOX9 in hypoxic PH in rats. The findings revealed that SOX9 was upregulated in the pulmonary arteries and PASMCs of hypoxia-exposed rats. SOX9 knockdown inhibited hypoxia-induced proliferation and migration of PASMCs, reduced PVR, and subsequently alleviated hypoxia-induced PH in rats, suggesting that SOX9 plays a critical role in PH. Further investigation demonstrated that SOX9 interacted with DPP4, preventing its ubiquitin degradation in hypoxia-exposed PASMCs. DPP4 knockdown inhibited hypoxia-induced PASMC proliferation and migration, and administration of the DPP4 inhibitor sitagliptin (5 mg/kg) significantly reduced PVR and alleviated hypoxia-induced PH in rats, indicating that SOX9 contributes to PH by stabilizing DPP4. The results also showed that hypoxia induced YAP1 expression and dephosphorylation, leading to YAP1 nuclear localization. YAP1 knockdown promoted the degradation of HIF-1α in hypoxia-exposed PASMCs and inhibited hypoxia-induced proliferation and migration of PASMCs. Additionally, HIF-1α, as a transcription factor, promoted SOX9 expression by binding to the SOX9 promoter in hypoxia-exposed PASMCs. In conclusion, hypoxia promotes the proliferation and migration of PASMCs through the regulation of the YAP1/HIF-1α/SOX9/DPP4 signaling pathway, leading to PH in rats. These findings suggest that SOX9 may serve as a potential prognostic marker and therapeutic target for PH.
肺动脉高压（PH）是一种进行性心肺疾病，其特征为肺血管重构（PVR），主要是由于肺动脉平滑肌细胞（PASMCs）的过度增殖。本研究旨在探讨 SOX9 在大鼠低氧性 PH 中的作用及其分子机制。结果显示，SOX9 在低氧暴露大鼠的肺动脉和 PASMCs 中上调。SOX9 敲低抑制了 PASMC 低氧诱导的增殖和迁移，降低了 PVR，随后减轻了大鼠低氧性 PH，表明 SOX9 在 PH 中起关键作用。进一步研究表明，SOX9 与 DPP4 相互作用，防止其在低氧暴露的 PASMCs 中发生泛素降解。DPP4 敲低抑制了 PASMC 低氧诱导的增殖和迁移，给予 DPP4 抑制剂西他列汀（5mg/kg）可显著降低 PVR，并减轻大鼠低氧性 PH，表明 SOX9 通过稳定 DPP4 促进 PH 的发生。结果还显示，低氧诱导 YAP1 表达和去磷酸化，导致 YAP1 核定位。YAP1 敲低促进了低氧暴露的 PASMCs 中 HIF-1α 的降解，并抑制了 PASMCs 的低氧诱导增殖和迁移。此外，HIF-1α 作为转录因子，通过结合低氧暴露的 PASMCs 中 SOX9 启动子，促进 SOX9 的表达。总之，低氧通过调节 YAP1/HIF-1α/SOX9/DPP4 信号通路促进 PASMCs 的增殖和迁移，导致大鼠 PH。这些发现表明，SOX9 可能作为 PH 的一个潜在预后标志物和治疗靶点。
