4-hydroxynonenal Prevents NO Production in Vascular Smooth Muscle Cells by Inhibiting Nuclear Factor-kappaB-dependent Transcriptional Activation of Inducible NO Synthase

The role of lipid peroxidation products in atherogenesis was studied. We investigated whether 4-hydroxy-2-nonenal (HNE) modulates activation of the nuclear factor (NF)-kappaB system or alters expression of the NF-kappaB target gene product, inducible NO synthase (iNOS), in vascular smooth muscle cells (VSMCs) stimulated by lipopolysaccharide (LPS) in combination with interferon (IFN)-gamma (LPS/IFN). NO production induced by LPS/IFN was dose-dependently inhibited by HNE. NF-kappaB activation by LPS/IFN was inhibited by HNE in a dose-dependent manner. HNE significantly decreased LPS/IFN-stimulated proteolysis of IkappaB-alpha. iNOS promoter activity stimulated by LPS/IFN was also decreased by HNE dose-dependently. The treatment of VSMCs with LPS/IFN strongly stimulated iNOS mRNA and protein expression. The LPS/IFN-induced increases in iNOS mRNA and protein levels were dose-dependently decreased by HNE. Our data suggest that treatment with HNE blocks signaling events required for IkappaB-alpha degradation, thereby preventing NF-kappaB activation. Inhibition of NF-kappaB-regulated gene expression, especially modulation of NO production, may contribute to atherogenesis.