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

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.

• Authors: Fei Mao, Bo Han, Diandong Jiang, Xiaoli Zhang, Tingting Pang, Youfei Fan
• Journal: Cardiovascular drugs and therapy (Cardiovasc Drugs Ther) Vol. 34 Issue 1 Pg. 41-52 (02 2020) ISSN: 1573-7241 [Electronic] United States
• PMID: 32096002 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• BAX protein, human
• BCL2 protein, human
• BMPER protein, human
• Bone Morphogenetic Proteins
• Carrier Proteins
• Homeodomain Proteins
• MSX2 protein
• Phosphodiesterase 5 Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Smad Proteins, Receptor-Regulated
• bcl-2-Associated X Protein
• Vardenafil Dihydrochloride
• Hydrogen Peroxide
• Bone Morphogenetic Protein Receptors

Topics

• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Bone Morphogenetic Protein Receptors (metabolism)
• Bone Morphogenetic Proteins (metabolism)
• Carrier Proteins (metabolism)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Homeodomain Proteins (metabolism)
• Human Umbilical Vein Endothelial Cells (drug effects, metabolism, pathology)
• Humans
• Hydrogen Peroxide (toxicity)
• Oxidative Stress (drug effects)
• Phosphodiesterase 5 Inhibitors (pharmacology)
• Phosphorylation
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Signal Transduction
• Smad Proteins, Receptor-Regulated (metabolism)
• Vardenafil Dihydrochloride (pharmacology)
• bcl-2-Associated X Protein (metabolism)