Department of Pediatrics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
Department of Emergency Center, Hunan Children's Hospital, Changsha, Hunan, China.
J Cardiovasc Pharmacol. 2019 Oct;74(4):355-363. doi: 10.1097/FJC.0000000000000714.
The dysregulation of pulmonary arterial vasoactive mediators or excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) might result in contraction or remodeling of pulmonary blood vessels, leading to related lung diseases. Recent studies suggest that hydrogen sulfide (H2S), a gaseous vasodilator generated in the blood vessels by the enzymes cystathionine γ-lyase (CSE) and cystathionine-β-synthase (CBS), could induce the vasodilation, thus improving contraction or remodeling-induced lung diseases. In this study, we hypothesized that PASMCs could produce H2S and relax the pulmonary artery, and its mechanism is related to CSE, CBS, and TRPV4 channels by affecting both the excessive proliferation and pulmonary vasoconstriction in PASMCs. We found that the sildenafil treatment could remarkably promote H2S production and control the proliferation in PASMCs; meanwhile, the protein levels of CSE and CBS and the intracellular concentration of calcium could also be increased by sildenafil. Moreover, the effects of sildenafil could be reversed by a CBS inhibitor or a CSE inhibitor, indicating that sildenafil could affect CSE and CBS to modulate the production of H2S and the proliferation in rat PASMCs. Together, we demonstrated a new mechanism for sildenafil to modulate the synthesis of H2S and cell proliferation in PASMCs by affecting CSE and CBS. TRPV4-dependent Ca events and BMP4 may also be involved.
肺血管活性介质失调或肺动脉平滑肌细胞（PASMC）过度增殖可能导致肺血管收缩或重塑，进而引发相关肺部疾病。最近的研究表明，硫化氢（H2S）作为一种在血管中由胱硫醚γ-裂解酶（CSE）和胱硫醚-β-合酶（CBS）生成的气体血管扩张剂，可诱导血管舒张，从而改善收缩或重塑引起的肺部疾病。在本研究中，我们假设 PASMC 可以产生 H2S 并使肺动脉松弛，其机制可能与 CSE、CBS 和 TRPV4 通道有关，可同时影响 PASMC 的过度增殖和肺血管收缩。我们发现西地那非治疗可显著促进 H2S 的产生并控制 PASMC 的增殖；同时，西地那非还可增加 CSE 和 CBS 的蛋白水平以及细胞内钙离子浓度。此外，CBS 抑制剂或 CSE 抑制剂可逆转西地那非的作用，表明西地那非可通过影响 CSE 和 CBS 来调节 H2S 的产生和大鼠 PASMC 的增殖。综上，我们证实了西地那非通过影响 CSE 和 CBS 来调节 PASMC 中 H2S 合成和细胞增殖的新机制。TRPV4 依赖性 Ca 事件和 BMP4 也可能参与其中。
