Additionally, reductions in NO, eNOS phosphorylation (serine1177) and eNOS protein expression were also observed in HMGB-1 endothelium-specific knockout mouse aortae and HUVECs transfected with HMGB-1 silencing RNA [58], thus suggesting that intracellular and extracellular HMGB-1 have opposing effects on endothelial cells, and targeting extracellular HMGB-1 may improve endothelial dysfunction during HHcy and atherogenesis by reducing inflammation and cellular stress. This evidence concerns the gene HMGB1 and endothelial dysfunction.