The aim of the present study was to investigate the effects of 4-hydroxy-2-nonenal (4-HNE) on tube formation by human bone marrow endothelial cells (HBMEC). We found that 4-HNE at physiologically achievable concentrations (5 and 10 mu M) inhibited the formation of tubes. Western blot analysis revealed that inhibition of tube formation by 4-HNE was associated with increased expression of chondromodulin-I (CHM-1), a protein with well-known anti-angiogenic properties. Cell viability assays showed that 4-HNE at concentrations of 10 mu M or less did not cause HBMEC cell death. Luciferase reporter assays did not show any inducing effect of 4-HNE on the promoter activity of human CHM-1 gene indicating that post-transcriptional or post-translational modifications may account for the up-regulation of CHM-1. Collectively, the results of the present study show for the first time that 4-HNE inhibits tube formation by HBMECs indicating a potential anti-angiogenic activity of 4-HNE. This inhibition occurs at least in part via 4-HNE-induced CHM-I protein expression. (C) 2008 Elsevier Inc. All rights reserved.