Department of Respiration, Wuxi People's Hospital Affiliated to Nanjing Medical University, 214023, Wuxi, China.
Hypertens Res. 2018 Sep;41(9):691-698. doi: 10.1038/s41440-018-0068-7. Epub 2018 Jun 27.
Angiogenesis and activation of vascular endothelial growth factor (VEGF) signaling are tightly regulated under the condition of hypoxic pulmonary hypertension (HPH); therefore, deciphering the regulatory mechanisms associated with VEGF is important. SET domain-containing 3 (SETD3) and VEGF expression in lung tissue during hypoxia exposure and lentivirus. SETD3 treatments were detected by real-time PCR and Western blot analysis. Remodeling of pulmonary vasculature and hypertrophy of the RV were evaluated. The effects of SETD3 over-expression on the interaction between SETD3 and forkhead box protein M1 (FoxM1) at the VEGF promoter and downstream of the VEGF signal pathway during chronic hypoxia were detected. SETD3 lentiviral vector treatment not only inhibited the increase in VEGF expression but also significantly relieved pulmonary vasculature remodeling and hypertrophy of the RV during HPH. The functional interplay between SETD3 and FoxM1 on chromatin may negatively regulate VEGF expression under HPH through the VEGF receptor-extracellular signal-regulated kinase-hypoxia-induced factor-1 signal pathway. SETD3-mediated transcriptional modification of VEGF may be a potential target to inhibit the development of HPH.
血管生成和血管内皮生长因子 (VEGF) 信号的激活在低氧性肺动脉高压 (HPH) 条件下受到严格调控；因此，破译与 VEGF 相关的调节机制很重要。通过实时 PCR 和 Western blot 分析检测缺氧暴露和慢病毒时肺组织中的 SET 域包含蛋白 3 (SETD3) 和 VEGF 的表达。评估肺血管重塑和 RV 肥大。检测 SETD3 过表达对慢性低氧时 VEGF 启动子和 VEGF 信号通路下游 SETD3 与叉头框蛋白 M1 (FoxM1) 之间相互作用的影响。SETD3 慢病毒载体治疗不仅抑制了 VEGF 表达的增加，而且在 HPH 期间还显著缓解了肺血管重塑和 RV 肥大。在 HPH 下，SETD3 和 FoxM1 之间的功能相互作用可能通过 VEGF 受体-细胞外信号调节激酶-低氧诱导因子-1 信号通路负调控 VEGF 表达。SETD3 介导的 VEGF 转录修饰可能是抑制 HPH 发展的潜在靶点。
