Department of Neonatalogy, Qilu Children's Hospital of ShanDong University, ShanDong, China.
Department of Pediatrics Research Institute, Qilu Children's Hospital of ShanDong University, ShanDong, China; and.
J Cardiovasc Pharmacol. 2023 Mar 1;81(3):232-239. doi: 10.1097/FJC.0000000000001373.
Persistent pulmonary hypertension of the newborn (PPHN) is characterized by pulmonary arterial remodeling mainly because of apoptosis resistance and excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). Sildenafil is a phosphodiesterase-5 inhibitor. Some reports have shown that sildenafil exerts protective effects against PPHN. However, the function of sildenafil in PPHN and the underlying molecular mechanisms is not clear. Here, we revealed that sildenafil effectively suppressed hypoxia-induced PASMC proliferation and apoptosis inhibition ( P < 0.05). Also, sildenafil obviously reduced ventricular hypertrophy, and inhibited pulmonary vascular remodeling in the PPHN model ( P < 0.05). Moreover, sildenafil treatment significantly attenuated the induction of Notch3 and Hes1 induced by hypoxia treatment ( P < 0.05). Furthermore, overexpression of Notch3 abolished the reduction of PASMC proliferation and promotion of PASMC apoptosis induced by sildenafil under hypoxia ( P < 0.05), whereas knockdown of Notch3 had an opposite effect ( P < 0.05). Together, our study demonstrates that sildenafil shows a potential benefit against the development of PPHN by inhibiting Notch3 signaling, providing a strategy for treating PPHN in the future.
新生儿持续性肺动脉高压（PPHN）的特征是肺血管重塑，主要是由于肺动脉平滑肌细胞（PASMCs）的凋亡抵抗和过度增殖。西地那非是一种磷酸二酯酶-5 抑制剂。一些报告表明，西地那非对 PPHN 具有保护作用。然而，西地那非在 PPHN 中的作用及其潜在的分子机制尚不清楚。在这里，我们发现西地那非能有效抑制低氧诱导的 PASMC 增殖和凋亡抑制（P<0.05）。此外，西地那非明显减轻了 PPHN 模型中的心室肥厚，并抑制了肺血管重塑（P<0.05）。而且，西地那非处理显著减弱了低氧处理诱导的 Notch3 和 Hes1 的诱导（P<0.05）。此外，Notch3 的过表达消除了西地那非在低氧下对 PASMC 增殖的抑制和促进 PASMC 凋亡的作用（P<0.05），而 Notch3 的敲低则有相反的效果（P<0.05）。总之，我们的研究表明，西地那非通过抑制 Notch3 信号通路显示出对 PPHN 发展的潜在益处，为未来治疗 PPHN 提供了一种策略。
