doi: 10.1161/hq0901.095278
© 2001 American Heart Association, Inc.
Vascular Biology |
Signaling Mechanisms of Nuclear Factor-
B-Mediated Activation of Inflammatory Genes by 13-Hydroperoxyoctadecadienoic Acid in Cultured Vascular Smooth Muscle Cells
From the Gonda Diabetes Center (R.N., M.A.R.), Beckman Research Institute of the City of Hope, Duarte, Calif; University of Tennessee (K.U.K., S.F.), Memphis; Emory University (B.V.K.), Atlanta, Ga.
Correspondence to Rama Natarajan, PhD, Gonda Diabetes Center, Beckman Research Institute of the City of Hope, 1500 East Duarte Rd, Duarte, CA 91010. E-mail rnatarajan{at}coh.org
Abstract—— Oxidatively modified low density lipoprotein (LDL) has been implicated in the pathogenesis of atherosclerosis. LDL oxidation may be mediated by several factors, including cellular lipoxygenases. The lipoxygenase product of linoleic acid, 13-hydroperoxyoctadecadienoic acid (13-HPODE), is a significant component of oxidized LDL and has been shown to be present in atherosclerotic 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-activated protein kinases, extracellular signal-regulated kinase 1/2, p38, and c-Jun amino-terminal kinase, in porcine VSMCs. 13-HPODE also specifically activated the oxidant stress-responsive transcription factor, nuclear factor-
B, but not activator protein-1 or activator protein-2. 13-HPODE-induced nuclear factor-B DNA binding activity was blocked by an antioxidant, N-acetylcysteine, as well as an inhibitor of protein kinase C. 13-HPODE, but not the hydroxy product, 13-(S)-hydroxyoctadecadienoic acid, also dose-dependently increased vascular cell adhesion molecule-1 promoter activation. This was inhibited by an antioxidant as well as by inhibitors of Ras p38 mitogen-activated protein kinase and protein kinase C. Our results suggest that oxidized lipid components of oxidized LDL, such as 13-HPODE, may play a key role in the atherogenic process by inducing the transcriptional regulation of inflammatory genes in VSMCs via the activation of key signaling kinases.
Key Words: oxidized LDL • 13-hydroperoxyoctadecadienoic acid • NF-B • mitogen-activated protein kinase • atherosclerosis
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