Aim To investigate the role of the p38 mitogen-activated protein kinase(p38MAPK) on the high glucose-mediated damage to human umbilical vein endothelial cell(hUVEC) and to investigate the effect of the protein kinase C(PKC) dependent pathway on the activation of glucose on p38MAPK. Methods HUVEC were isolated from umbilical cords of normal pregnancies. HUVEC were exposed for 72 h to 5 m(control),22 mmol/L glucose(HG),phorbol myristate acetate(PMA,a PKC agonist),GF109203X(a general PKC-specific inhibitor),SB₂03580(a p38MAPK-specific inhibitor).The expression of phospho-p38MAPK protein and p38MAPK mRNA were detected by Western-blot and reverse transcription polymerase chain reaction(RT-PCR)respectively.The apoptosis of hUVEC were quantitated by flow cytometry using propidium iodid staining. Results Hight glucose and PMA increased the expression of phospho-p38MAPK,p38MAPK mRNA and apoptosis of hUVEC significantly.Incubation of hUVEC with high glucose for 72 h increased the expression of phospho-p38MAPK,p38MAPK mRNA and apoptosis of hUVEC(0.605±0.0407,0.447±0.0252, 16.8%) versus incubation with low glucose(0.189±0.0103,0.313±0.0153,5.15%,p<0.05) respectively.But the expression of phospho-p38MAPK,p38MAPK mRNA and apoptosis of hUVEC were inhibited by GF109203X and SB₂03580. Conclusions The activation of p38MAPK may accelerate the high glucosemediated damage to hUVEC.Hyperglycemia can partly activate p38MAPK by PKC dependent pathway.p38MAPK-specific inhibitor may protect hUVEC in the high glucose-mediated damage.