Signaling mechanisms of nuclear factor-kappa B-mediated activation of inflammatory genes by 13-hydroperoxyoctadecadienoic acid in cultured vascular smooth muscle cells

Oxidatively modified low density lipoprotein (LDL) has been implicated in t he pathogenesis of atherosclerosis. LDL oxidation may be mediated by severa l factors, including cellular lipoxygenases. The lipoxygenase product of li noleic acid, 13-hydroperoxyoctadecadienoic acid (13-HPODE), is a significan t component of oxidized LDL and has been shown to be present in atheroscler otic lesions. However, the mechanism of action of these oxidized lipids in vascular smooth muscle cells (VSMCs) is not clear. In the present study, we show that 13-HPODE leads to the activation of Ras as well as the mitogen-a ctivated protein kinases, extracellular signal-regulated kinase 1/2, p38, a nd c-Jun amino-terminal kinase, in porcine VSMCs. 13-HPODE also specificall y activated the oxidant stress-responsive transcription factor, nuclear fac tor-kappaB, but not activator protein-1 or activator protein-2. 13-HPODE-in duced nuclear factor-kappaB DNA binding activity was blocked by an antioxid ant, N-acetyleysteine, as well as an inhibitor of protein kinase C. 13-HPOD E, but not the hydroxy product, 13-(S)-hydroxyoctadecadienoic acid, also do se-dependently increased vascular cell adhesion molecule-1 promoter activat ion. This was inhibited by an antioxidant as well as by inhibitors of Ras p 38 mitogen-activated protein kinase and protein kinase C. Our results sugge st that oxidized lipid components of oxidized LDL, such as 13-HPODE, may pl ay a key role in the atherogenic process by inducing the transcriptional re gulation of inflammatory genes in VSMCs via the activation of key signaling kinases.