BACKGROUND Endothelial dysfunction,a hallmark of diabetes,is a critical and initiating contributor to the pathogenesis of diabetic cardiovascular complications.However,the underlying mechanisms are still not fully und...BACKGROUND Endothelial dysfunction,a hallmark of diabetes,is a critical and initiating contributor to the pathogenesis of diabetic cardiovascular complications.However,the underlying mechanisms are still not fully understood.Ferroptosis is a newly defined regulated cell death driven by cellular metabolism and irondependent lipid peroxidation.Although the involvement of ferroptosis in disease pathogenesis has been shown in cancers and degenerative diseases,the participation of ferroptosis in the pathogenesis of diabetic endothelial dysfunction remains unclear.AIM To examine the role of ferroptosis in diabetes-induced endothelial dysfunction and the underlying mechanisms.METHODS Human umbilical vein endothelial cells(HUVECs)were treated with high glucose(HG),interleukin-1β(IL-1β),and ferroptosis inhibitor,and then the cell viability,reactive oxygen species(ROS),and ferroptosis-related marker protein were tested.To further determine whether the p53-xCT(the substrate-specific subunit of system Xc-)-glutathione(GSH)axis is involved in HG and IL-1βinduced ferroptosis,HUVECs were transiently transfected with p53 small interfering ribonucleic acid or NC small interfering ribonucleic acid and then treated with HG and IL-1β.Cell viability,ROS,and ferroptosis-related marker protein were then assessed.In addition,we detected the xCT and p53 expression in the aorta of db/db mice.RESULTS It was found that HG and IL-1βinduced ferroptosis in HUVECs,as evidenced by the protective effect of the ferroptosis inhibitors,Deferoxamine and ferrostatin-1,resulting in increased lipid ROS and decreased cell viability.Mechanistically,activation of the p53-xCT-GSH axis induced by HG and IL-1βenhanced ferroptosis in HUVECs.In addition,a decrease in xCT and the presence of deendothelialized areas were observed in the aortic endothelium of db/db mice.CONCLUSION Ferroptosis is involved in endothelial dysfunction and p53-xCT-GSH axis activation plays a crucial role in endothelial cell ferroptosis and endothelial dysfunction.展开更多
基金National Natural Science Foundation of China,No.81800244 and No.81670237.
文摘BACKGROUND Endothelial dysfunction,a hallmark of diabetes,is a critical and initiating contributor to the pathogenesis of diabetic cardiovascular complications.However,the underlying mechanisms are still not fully understood.Ferroptosis is a newly defined regulated cell death driven by cellular metabolism and irondependent lipid peroxidation.Although the involvement of ferroptosis in disease pathogenesis has been shown in cancers and degenerative diseases,the participation of ferroptosis in the pathogenesis of diabetic endothelial dysfunction remains unclear.AIM To examine the role of ferroptosis in diabetes-induced endothelial dysfunction and the underlying mechanisms.METHODS Human umbilical vein endothelial cells(HUVECs)were treated with high glucose(HG),interleukin-1β(IL-1β),and ferroptosis inhibitor,and then the cell viability,reactive oxygen species(ROS),and ferroptosis-related marker protein were tested.To further determine whether the p53-xCT(the substrate-specific subunit of system Xc-)-glutathione(GSH)axis is involved in HG and IL-1βinduced ferroptosis,HUVECs were transiently transfected with p53 small interfering ribonucleic acid or NC small interfering ribonucleic acid and then treated with HG and IL-1β.Cell viability,ROS,and ferroptosis-related marker protein were then assessed.In addition,we detected the xCT and p53 expression in the aorta of db/db mice.RESULTS It was found that HG and IL-1βinduced ferroptosis in HUVECs,as evidenced by the protective effect of the ferroptosis inhibitors,Deferoxamine and ferrostatin-1,resulting in increased lipid ROS and decreased cell viability.Mechanistically,activation of the p53-xCT-GSH axis induced by HG and IL-1βenhanced ferroptosis in HUVECs.In addition,a decrease in xCT and the presence of deendothelialized areas were observed in the aortic endothelium of db/db mice.CONCLUSION Ferroptosis is involved in endothelial dysfunction and p53-xCT-GSH axis activation plays a crucial role in endothelial cell ferroptosis and endothelial dysfunction.
