Department of Pediatrics, Shandong Provincial Hospital affiliated to Shandong University, Shandong University, Jinan, 250014, People's Republic of China.
Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, People's Republic of China.
Cardiovasc Drugs Ther. 2020 Feb;34(1):41-52. doi: 10.1007/s10557-020-06939-5.
The pleiotropic roles of phosphodiesterase-5 inhibitors (PDE5is) in cardiovascular diseases have attracted attention. The effect of vardenafil (a PDE5i) is partly mediated through reduced oxidative stress, but it is unclear whether vardenafil protects against hydrogen peroxide (HO)-induced endothelial cell injury, and the molecular mechanisms that are involved remain unknown. We determined the protective role of vardenafil on HO-induced endothelial cell injury in cultured human umbilical vein endothelial cells (HUVECs).
Vardenafil decreased the number of TUNEL-positive cells, increased the Bcl2/Bax ratio, and ameliorated the numbers of BrdU-positive cells in HO-treated HUVECs. The bone morphogenetic protein receptor (BMPR)/p-Smad/MSX2 pathway was enhanced in response to HO, and vardenafil treatment could normalize this pathway. To determine whether the BMP pathway is involved, we blocked the BMP pathway using dorsomorphin, which abolished the protective effects of vardenafil. We found that vardenafil improved the HO-induced downregulation of BMP-binding endothelial regulator protein (BMPER), which possibly intersects with the BMP pathway in the regulation of endothelial cell injury in response to oxidative stress.
We demonstrated for the first time that exogenous HO activates BMPR expression and promotes Smad1/5/8 phosphorylation. Additionally, vardenafil can attenuate HO-induced endothelial cell injury in HUVECs. Vardenafil decreases apoptosis through an improved Bcl-2/Bax ratio and increases cell proliferation. Vardenafil protects against endothelial cell injury through ameliorating the intracellular oxidative stress level and BMPER expression. The protective role of vardenafil on HO-induced endothelial cell injury is mediated through BMPR/p-Smad/MSX2 in HUVECs.
磷酸二酯酶 5 抑制剂（PDE5i）在心血管疾病中的多效作用引起了关注。伐地那非（一种 PDE5i）的作用部分通过降低氧化应激来介导，但尚不清楚伐地那非是否可以预防过氧化氢（HO）诱导的内皮细胞损伤，以及涉及的分子机制仍不清楚。我们确定了伐地那非在培养的人脐静脉内皮细胞（HUVEC）中对 HO 诱导的内皮细胞损伤的保护作用。
伐地那非减少了 TUNEL 阳性细胞的数量，增加了 Bcl2/Bax 比值，并改善了 HO 处理的 HUVEC 中 BrdU 阳性细胞的数量。骨形态发生蛋白受体（BMPR）/p-Smad/MSX2 途径在 HO 作用下增强，伐地那非处理可以使该途径正常化。为了确定 BMP 途径是否参与其中，我们使用 Dorsomorphin 阻断 BMP 途径，这消除了伐地那非的保护作用。我们发现伐地那非改善了 HO 诱导的 BMP 结合内皮调节蛋白（BMPER）下调，这可能在调节内皮细胞对氧化应激的损伤方面与 BMP 途径相交。
我们首次证明外源性 HO 激活 BMPR 表达并促进 Smad1/5/8 磷酸化。此外，伐地那非可以减轻 HUVEC 中 HO 诱导的内皮细胞损伤。伐地那非通过改善 Bcl-2/Bax 比值减少细胞凋亡并增加细胞增殖。伐地那非通过改善细胞内氧化应激水平和 BMPER 表达来保护内皮细胞免受损伤。伐地那非对 HO 诱导的内皮细胞损伤的保护作用是通过 BMPR/p-Smad/MSX2 在 HUVEC 中介导的。
