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Documented studies have suggested that NADPH oxidases (NOXs) NOX1,NOX2,and NOX5 promote vessel wall apoptosis,whereas the role of NOX4 remains controver-sial.In this study,we studied the role of NOX4 in tert-butyl hydroperoxide (t-BHP)-induced cell death in human umbili-cal vein endothelial cells (HUVECs).T-BHP dramatically induced caspase-dependent apoptosis,as evidenced by An-nexin V/PI staining and Western blot.T-BHP increased NOX activity and induced reactive oxygen species (ROS) generation,which was inhibited by NAC and DPI.Further-more,t-BHP induced NOX4 expression and membrane translocations.Silencing of NOX4 with siRNA significantly in-hibited t-BHP-induced ROS generation and cell death.T-BHP induced sustained phosphorylation of p38MAPK,which was abolished by NOX4 siRNA.Inhibition of p38MAPK by SB203580 reversed t-BHP-induced increase in caspase-3/-7 activity.In addition,decreased cell death and caspase-3/-7 activity were observed in NOX4-overexpressed cells in re-sponse to t-BHP.Interestingly,the phosphorylation of Akt was not altered by t-BHP in normal endothelial cells but sig-nificantly increased in NOX4-overexpressed cells.The Akt inhibitor enhanced cell death in response to t-BHP in NOX4-overexpressed cells.T-BHP induced NOX4-dependent apoptosis in HUVECs mediated by p38MAPK activation.Constitutive expression of NOX4 protected endothelial death in response to t-BHP by activating Akt.These results pro-vided novel mechanisms for the dual roles of NOX4 in car-diovascular diseases.