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.
Highlights
Transporter, Zrt/Irt-related protein 8 (ZIP8), Mediated by the ALK5-Smad2/3 and ALK5-Smad3p38 mitogen-activated protein kinase (MAPK) Signal Pathways in Cultured Vascular Endothelial Cells
transforming growth factor (TGF)-β1 increased the intracellular accumulation of cadmium in vascular endothelial cells after exposure to cadmium (Figure 1c), which suggests that TGF-β1 potentiated cadmium cytotoxicity in vascular endothelial cells through increased intracellular cadmium accumulation
Since TGF-β1 is released from α-granules of platelets that aggregate at the damaged vascular endothelial monolayers, modification of cadmium cytotoxicity against vascular endothelial cells by TGF-β1 appears important to facilitate understanding of the damage to the cells caused by cadmium while the damaged endothelium is being repaired
Summary
Transporter, ZIP8, Mediated by the ALK5-Smad2/3 and ALK5-Smad3p38 MAPK Signal Pathways in Cultured Vascular Endothelial Cells. 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. 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. If cells are exposed to toxic substances, such as heavy metals, during this repair process, TGF-β1 may affect their published maps and institutional affiliations
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