4-hydroxynonenal prevents NO production in vascular smooth muscle cells byinhibiting nuclear factor-kappa B-dependent transcriptional activation of inducible NO synthase
Y. Hattori et al., 4-hydroxynonenal prevents NO production in vascular smooth muscle cells byinhibiting nuclear factor-kappa B-dependent transcriptional activation of inducible NO synthase, ART THROM V, 21(7), 2001, pp. 1179-1183
The role of lipid peroxidation products in atherogenesis was studied. We in
vestigated whether 4-hydroxy-2-nonenal (HNE) modulates activation of the nu
clear factor (NF)-kappaB system or alters expression of the NF-kappaB targe
t gene product, inducible NO synthase (iNOS), in vascular smooth muscle cel
ls (VSMCs) stimulated by lipopolysaccharide (LPS) in combination with inter
feron (IFN)-gamma (LPS/IFN). NO production induced by LPS/IFN was dose-depe
ndently inhibited by HNE. NF-kappaB activation by LPS/IFN was inhibited by
HNE in a dose-dependent manner. HNE significantly decreased LPS/IFN-stimula
ted proteolysis of I kappaB-alpha. iNOS promoter activity stimulated by LPS
/IFN was also decreased by HNE dose-dependently. The treatment of VSMCs wit
h LPS/IFN strongly stimulated iNOS mRNA and protein expression. The LPS/IFN
-induced increases in iNOS mRNA and protein levels were dose-dependently de
creased by HNE, Our data suggest that treatment with HNE blocks signaling e
vents required for I kappaB-alpha degradation, thereby preventing NF-kappaB
activation. Inhibition of NF-kappaB-regulated gene expression, especially
modulation of NO production, may contribute to atherogenesis.