Augmented expression of inducible NO synthase in vascular smooth muscle cells during aging is associated with enhanced NF-kappa B activation

Vascular smooth muscle cells (SMCs) are important targets for endothelium-d erived nitric oxide (NO), but this production is attenuated in injured and diseased arteries and during aging. However, SMCs can produce NO themselves by expressing an inducible form of NO synthase (iNOS) under inflammatory c onditions and in the repair process after arterial injury. We examined iNOS expression in SMCs derived from the aortic media of newborn, young adult, and old rats. Our results show that SMCs from newborn rats cannot produce s ignificant amounts of NO on stimulation with interferon-gamma plus lipopoly saccharide or interleukin-1 beta. In contrast, SMCs from old rats exhibit m arkedly enhanced iNOS activity. The difference in iNOS activity between the newborn and the old SMCs was closely correlated with levels of iNOS protei n, mRNA, and gene promoter activity. Similarly, intercellular adhesion mole cule-1 (ICAM-1) was also expressed more abundantly in the old than in the n ewborn SMCs in response to cytokines. Both iNOS and ICAM-1 are transcriptio nally regulated by nuclear factor kappa B (NF-kappa B). Our data demonstrat e an intense transactivation of NF-kappa B in old SMCs on tumor necrosis fa ctor-alpha stimulation but only a weak one in newborn SMCs. The difference in the NF-kappa B activation could be explained by a much faster and more e xtensive I kappa B alpha degradation in old than in newborn SMCs. These dat a indicate that the capability to respond to proinflammatory stimuli by act ivating NF-kappa B differs between SMCs at different stages of development. This results in differential capability to express NF-kappa B-dependent ge nes such as iNOS and ICAM-1, which could have implications for host defense and the pathogenesis of vascular diseases.