© 1999 American Heart Association, Inc.
Vascular Biology |
Augmented Expression of Inducible NO Synthase in Vascular Smooth Muscle Cells During Aging Is Associated With Enhanced NF-
B Activation
From the Cardiovascular Research Laboratory (Z.-q.Y., A.S., G.K.H.), Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden, and the Department of Pathology (M.-L.B.-P., G.G.), University of Geneva, Geneva, Switzerland.
Correspondence to Dr Zhong-qun Yan, Center for Molecular Medicine (L8:03). Karolinska Hospital, S-17176 Stockholm, Sweden. E-mail zhong-qun.yan{at}cmm.ki.se
Abstract—Vascular smooth muscle
cells (SMCs) are important targets for
endothelium-derived 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 conditions 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 significant amounts of NO on stimulation with
interferon-
plus lipopolysaccharide or interleukin-1ß. In
contrast, SMCs from old rats exhibit markedly enhanced iNOS activity.
The difference in iNOS activity between the newborn and the old SMCs
was closely correlated with levels of iNOS protein, mRNA, and gene
promoter activity. Similarly, intercellular adhesion molecule-1
(ICAM-1) was also expressed more abundantly in the old than in the
newborn SMCs in response to cytokines. Both iNOS and ICAM-1 are
transcriptionally regulated by nuclear factor 
B (NF-B). Our data
demonstrate an intense transactivation of NF-B in old SMCs on tumor
necrosis factor-
stimulation but only a weak one in newborn SMCs.
The difference in the NF-B activation could be explained by a much
faster and more extensive IB degradation in old than in newborn
SMCs. These data indicate that the capability to respond to
proinflammatory stimuli by activating NF-B differs between SMCs at
different stages of development. This results in differential
capability to express NF-B–dependent genes such as iNOS and ICAM-1,
which could have implications for host defense and the pathogenesis of
vascular diseases.
Key Words: age • vascular smooth muscle cells • nitric oxide • inducible nitric oxide synthase • nuclear factor-B
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