OBJECTIVE: Expression of adhesion molecules on endothelial cells and subsequent monocyte adhesion are initial events in the development of atherosclerosis. The purpose of this study was to investigate the role of apurinic/apyrmidinic endonuclease1/redox factor-1 (APE1/ref-1) in the interaction of monocytes with vascular endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVECs) were transfected with an adenovirus encoding human APE1/ref-1. The effect of APE1/ref-1 overexpression on monocyte adhesion, vascular cell adhesion molecule-1 (VCAM-1) protein expression, and intracellular superoxide production in tumor necrosis factor (TNF)-alpha-activated HUVECs was examined. RESULTS: Adhesion of the monocytic cell line U937 to TNF-alpha-stimulated HUVECs in which APE1/ref-1 was overexpressed was suppressed. APE1/ref-1 overexpression also suppressed expression of VCAM-1 induced by TNF-alpha. APE1/ref-1-mediated suppression of VCAM-1 was blocked by pretreatment with the nitric oxide synthase (NOS) inhibitor l-nitroarginine methyl ester. Furthermore, APE1/ref-1 overexpression inhibited the TNF-alpha-induced increase in intracellular superoxide and p38 MAPK phosphorylation. CONCLUSIONS: These data provide evidence that APE1/ref-1 in endothelial cells mitigates TNF-alpha-induced monocyte adhesion and expression of vascular cell adhesion molecules, and this anti-adhesive property of APE1/ref-1 is primarily mediated by a NOS-dependent mechanism. Furthermore, APE1/ref-1 may inhibit VCAM-1 expression by inhibiting superoxide production and p38 MAPK activation.