To investigate the potential role and underlying mechanism of Sirtuin2 (SIRT2) in regulating high glucose (HG)-induced vascular endothelial cell injury by using human umbilical vein endothelial cells (HUVECs). SIRT2 mRNA and protein expression levels were decreased in HG-treated HUVECs. SIRT2 overexpression increased viability, decreased apoptosis and reduced levels of reactive oxygen species in HG-treated HUVECs. SIRT2 overexpression decreased TNF-alpha expression (146.5 +/- 22.8 pg TNF-alpha ml(-1)) relative to that in the empty vector group (263.5 +/- 18.5 pg TNF-alpha ml(-1)) and decreased MCP-1 expression (63.8 +/- 9.85 pg MCP-1 ml(-1)) relative to that in the empty vector group (105.8 +/- 8.5 pg MCP-1 ml(-1)). SIRT2 overexpression decreased the acetylation of p53 by 33% and decreased the acetylation of NF-kappa B p65 by 58% in HG-treated HUVECs. SIRT2 prevents HG-induced vascular endothelial cell injury through suppressing the p53 and NF-kappa B signaling pathways.