Augmented expression of inducible NO synthase in vascular smooth muscle cells during aging is associated with enhanced NF-kappaB activation.
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-gamma plus lipopolysaccharide or interleukin-1beta. 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 kappaB (NF-kappaB). Our data demonstrate an intense transactivation of NF-kappaB in old SMCs on tumor necrosis factor-alpha stimulation but only a weak one in newborn SMCs. The difference in the NF-kappaB activation could be explained by a much faster and more extensive IkappaBalpha degradation in old than in newborn SMCs. These data indicate that the capability to respond to proinflammatory stimuli by activating NF-kappaB differs between SMCs at different stages of development. This results in differential capability to express NF-kappaB-dependent genes such as iNOS and ICAM-1, which could have implications for host defense and the pathogenesis of vascular diseases.
Yan
Z Q
ZQ
Cardiovascular Research Laboratory, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden. zhong-qun.yan@cmm.ki.se
Sirsjö
A
A
Bochaton-Piallat
M L
ML
Gabbiani
G
G
Hansson
G K
GK
D000375:Aging / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001013:Aorta, Thoracic / Q000166:cytology; D002478:Cells, Cultured; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology
D000949:Histocompatibility Antigens Class II; D016328:NF-kappa B; D012333:RNA, Messenger; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat