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Article

TGF-β1 Potentiates the Cytotoxicity of Cadmium by Induction of a Metal Transporter, ZIP8, Mediated by the ALK5-Smad2/3 and ALK5-Smad3-p38 MAPK Signal Pathways in Cultured Vascular Endothelial Cells

by
Keisuke Ito
1,†,
Tomoya Fujie
2,†,
Masahiro Shimomura
1,†,
Tsuyoshi Nakano
1,
Chika Yamamoto
2,* and
Toshiyuki Kaji
1,*
1
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan
2
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi 274-8510, Japan
*
Authors to whom correspondence should be addressed.
†
All authors contributed equally to this work.
Int. J. Mol. Sci. 2022, 23(1), 448; https://doi.org/10.3390/ijms23010448
Submission received: 12 November 2021 / Revised: 24 December 2021 / Accepted: 29 December 2021 / Published: 31 December 2021
(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Biochemistry)
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Abstract

Vascular endothelial cells cover the luminal surface of blood vessels in a monolayer and play a role in the regulation of vascular functions, such as the blood coagulation-fibrinolytic system. When the monolayer is severely or repeatedly injured, platelets aggregate at the damaged site and release transforming growth factor (TGF)-β1 in large quantities from their α-granules. Cadmium is a heavy metal that is toxic to various organs, including the kidneys, bones, liver, and blood vessels. Our previous study showed that the expression level of Zrt/Irt-related protein 8 (ZIP8), a metal transporter that transports cadmium from the extracellular fluid into the cytosol, is a crucial factor in determining the sensitivity of vascular endothelial cells to cadmium cytotoxicity. In the present study, TGF-β1 was discovered to potentiate cadmium-induced cytotoxicity by increasing the intracellular accumulation of cadmium in cells. Additionally, TGF-β1 induced the expression of ZIP8 via the activin receptor-like kinase 5-Smad2/3 signaling pathways; Smad3-mediated induction of ZIP8 was associated with or without p38 mitogen-activated protein kinase (MAPK). These results suggest that the cytotoxicity of cadmium to vascular endothelial cells increases when damaged endothelial monolayers that are highly exposed to TGF-β1 are repaired.
Keywords: cadmium; endothelial cell; Zrt- and Irt-like protein transporter; transforming growth factor-β1; Smad2/3; p38 MAPK cadmium; endothelial cell; Zrt- and Irt-like protein transporter; transforming growth factor-β1; Smad2/3; p38 MAPK

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MDPI and ACS Style

Ito, K.; Fujie, T.; Shimomura, M.; Nakano, T.; Yamamoto, C.; Kaji, T. TGF-β1 Potentiates the Cytotoxicity of Cadmium by Induction of a Metal Transporter, ZIP8, Mediated by the ALK5-Smad2/3 and ALK5-Smad3-p38 MAPK Signal Pathways in Cultured Vascular Endothelial Cells. Int. J. Mol. Sci. 2022, 23, 448. https://doi.org/10.3390/ijms23010448

AMA Style

Ito K, Fujie T, Shimomura M, Nakano T, Yamamoto C, Kaji T. TGF-β1 Potentiates the Cytotoxicity of Cadmium by Induction of a Metal Transporter, ZIP8, Mediated by the ALK5-Smad2/3 and ALK5-Smad3-p38 MAPK Signal Pathways in Cultured Vascular Endothelial Cells. International Journal of Molecular Sciences. 2022; 23(1):448. https://doi.org/10.3390/ijms23010448

Chicago/Turabian Style

Ito, Keisuke, Tomoya Fujie, Masahiro Shimomura, Tsuyoshi Nakano, Chika Yamamoto, and Toshiyuki Kaji. 2022. "TGF-β1 Potentiates the Cytotoxicity of Cadmium by Induction of a Metal Transporter, ZIP8, Mediated by the ALK5-Smad2/3 and ALK5-Smad3-p38 MAPK Signal Pathways in Cultured Vascular Endothelial Cells" International Journal of Molecular Sciences 23, no. 1: 448. https://doi.org/10.3390/ijms23010448

APA Style

Ito, K., Fujie, T., Shimomura, M., Nakano, T., Yamamoto, C., & Kaji, T. (2022). TGF-β1 Potentiates the Cytotoxicity of Cadmium by Induction of a Metal Transporter, ZIP8, Mediated by the ALK5-Smad2/3 and ALK5-Smad3-p38 MAPK Signal Pathways in Cultured Vascular Endothelial Cells. International Journal of Molecular Sciences, 23(1), 448. https://doi.org/10.3390/ijms23010448

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