Toxicology letters · 2019
Transient receptor potential melastatin 4 contributes to early-stage endothelial injury induced by arsenic trioxide.
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Yu Chun-Xiao, Zhang Yu-Yao, Wu Xia-Yang, Tang Hai-Xia, Liang Xue-Qi, Xue Zhou-Ming, Xue Ya-Dong, Li Jing, Zhu Hui, Huo Rong, Ban Tao
Аннотация
BACKGROUND/AIMS: To investigate the effect of Arsenic Trioxide (ATO) on endothelial cells injury and explore the role of transient receptor potential melastatin 4 channel (TRPM4) in ATO-induced endothelial injury.
METHODS: qRT-PCR was used to examine the mRNA expression of TRPM4 in human umbilical vein endothelial cells (HUVECs). The protein levels were measured by Western blot and immunostaining. The MTT, TUNEL, and transwell assays were used to evaluate the cell viability, apoptosis, and migration, respectively. The ultrastructural changes were observed by scanning electron microscopy. The membrane potential, cytosolic [Na+]i, cytosolic [Ca2+]i and reactive oxygen species (ROS) levels were detected by fluorescent probes. Isometric tension of mesenteric artery was recorded by using a multiwire myograph system.
RESULTS: ATO induced HUVEC cells injury, the significant upregulation of TRPM4 in this process was inhibited by 9-phenanthrol or siRNA. ATO-induced apoptosis and decrease in the cell viability/ migration were all partially reversed upon the treatment with 9-phenanthrol. Whereas, ATO-mediated increase in membrane potential, cytosolic [Na+]i, cytosolic [Ca2+]i and the ROS levels were also abolished by 9-phenanthrol or siRNA, suggesting that oxidative stress may be the potential mechanisms underlying ATO-induced endothelial injury. Additionally, 9-phenanthrol treatment prevented ATO-mediated impairment of acetylcholine-induced endothelium-dependent relaxations.
CONCLUSION: TRPM4 is involved in endothelial injury induced by ATO and may be a promising therapeutic target for endothelial injury.
METHODS: qRT-PCR was used to examine the mRNA expression of TRPM4 in human umbilical vein endothelial cells (HUVECs). The protein levels were measured by Western blot and immunostaining. The MTT, TUNEL, and transwell assays were used to evaluate the cell viability, apoptosis, and migration, respectively. The ultrastructural changes were observed by scanning electron microscopy. The membrane potential, cytosolic [Na+]i, cytosolic [Ca2+]i and reactive oxygen species (ROS) levels were detected by fluorescent probes. Isometric tension of mesenteric artery was recorded by using a multiwire myograph system.
RESULTS: ATO induced HUVEC cells injury, the significant upregulation of TRPM4 in this process was inhibited by 9-phenanthrol or siRNA. ATO-induced apoptosis and decrease in the cell viability/ migration were all partially reversed upon the treatment with 9-phenanthrol. Whereas, ATO-mediated increase in membrane potential, cytosolic [Na+]i, cytosolic [Ca2+]i and the ROS levels were also abolished by 9-phenanthrol or siRNA, suggesting that oxidative stress may be the potential mechanisms underlying ATO-induced endothelial injury. Additionally, 9-phenanthrol treatment prevented ATO-mediated impairment of acetylcholine-induced endothelium-dependent relaxations.
CONCLUSION: TRPM4 is involved in endothelial injury induced by ATO and may be a promising therapeutic target for endothelial injury.