Syndecan-4 is a heparan sulfate proteoglycan that is widely expressed in the vascular wall and as a cell surface receptor, modulates events relevant to acute tissue repair, including cell migration and proliferation, cell-substrate interactions, and matrix remodeling. While syndecan-4 expression is regulated in response to acute vascular wall injury, its regulation under chronic pro-atherogenic conditions, such as that characterized by prolonged exposure to oxidized lipids has not been defined. In this investigation arterial smooth muscle cells (SMC) were treated with 13-hydroperoxy-9,11-octadecadienoic acid (HPODE) and 13-hydroperoxy-10,12-octadecadienoic acid (HODE), oxidized products of linoleic acid, the major oxidizable fatty acid in LDL. Both oxidized fatty acids induced a dose-dependant rapid upregulation of syndecan-4 mRNA expression, which was not attenuated by cycloheximide. This response was inhibited by pre-treatment with N-acetylcysteine, catalase, or MEK1/2 inhibitors, but not by curcumin or lactacystin, known inhibitors of NFB. These data suggest that oxidized linoleic acid induces syndecan-4 mRNA expression through the initial generation of intracellular hydrogen peroxide with subsequent activation of the extracellular signal-regulated kinase (ERK) signalling pathway via MEK1/2. Notably, the HPODE-induced enhancement of syndecan-4 mRNA was accompanied by accelerated shedding of syndecan-4. In principle, alterations in both the cell surface expression and shedding of syndecan-4 may augment a variety of proatherogenic events that occur in response to oxidized lipids.