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The Phosphodiesterase-5 Inhibitor Vardenafil Improves the Activation of BMP Signaling in Response to Hydrogen Peroxide

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Abstract

Purpose

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 (H2O2)-induced endothelial cell injury, and the molecular mechanisms that are involved remain unknown. We determined the protective role of vardenafil on H2O2-induced endothelial cell injury in cultured human umbilical vein endothelial cells (HUVECs).

Methods and Results

Vardenafil decreased the number of TUNEL-positive cells, increased the Bcl2/Bax ratio, and ameliorated the numbers of BrdU-positive cells in H2O2-treated HUVECs. The bone morphogenetic protein receptor (BMPR)/p-Smad/MSX2 pathway was enhanced in response to H2O2, 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 H2O2-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.

Conclusions

We demonstrated for the first time that exogenous H2O2 activates BMPR expression and promotes Smad1/5/8 phosphorylation. Additionally, vardenafil can attenuate H2O2-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 H2O2-induced endothelial cell injury is mediated through BMPR/p-Smad/MSX2 in HUVECs.

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Acknowledgments

We also thank Jodi Smith, PhD, and Lisa Kreiner, PhD, from Liwen Bianji, Edanz Editing China (www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript.

Funding

The present study was financially supported by the Shandong Provincial Natural Science Foundation (project ZR2017PH026 and ZR2015PH010) and the National Natural Science Foundation of China (project 81700053).

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Authors and Affiliations

  1. Department of Pediatrics, Shandong Provincial Hospital affiliated to Shandong University, Shandong University, Jinan, 250014, People’s Republic of China

    Fei Mao, Bo Han, Diandong Jiang, Xiaoli Zhang, Tingting Pang & Youfei Fan

  2. Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, People’s Republic of China

    Fei Mao

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  1. Fei Mao
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Mao, F., Han, B., Jiang, D. et al. The Phosphodiesterase-5 Inhibitor Vardenafil Improves the Activation of BMP Signaling in Response to Hydrogen Peroxide. Cardiovasc Drugs Ther 34, 41–52 (2020). https://doi.org/10.1007/s10557-020-06939-5

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