Glycated serum albumin-induced nitric oxide production in vascular smooth muscle cells by nuclear factor kappaB-dependent transcriptional activation of inducible nitric oxide synthase.
Glycated proteins, including serum albumin, may be involved in the pathogenesis of diabetic vasculopathy. Recent evidence suggests that expression of inducible nitric oxide synthase (iNOS) in vascular smooth muscle cells (VSMC) may, in part, promote atherosclerosis by increasing local oxidative stress. We therefore investigated whether VSMC exposed to glycated human serum albumin (GHSA) produce nitric oxide (NO) by increasing iNOS expression through transcriptional activation of the iNOS gene and whether this process is dependent on nuclear factor kappaB (NF-kappaB) activation. Treatment of VSMC with GHSA causes activation of NF-kappaB and the iNOS promoter. Induction of NF-kappaB and the iNOS promoter by GHSA exhibited dose-dependent kinetics at concentrations ranging from 3 to 1000 microgram/ml. GHSA alone was a weak inducer of NO production in VSMC as measured by determining nitrite levels, and interferon-gamma alone was totally ineffective, whereas the combination of GHSA and interferon-gamma was a strong stimulus. This synergy for NO production corresponded to Northern blot analyses of iNOS mRNA expression. Thus, GHSA may promote atherosclerosis in part by activation of NF-kappaB and upregulation of iNOS, thereby fostering local inflammation and oxidative stress.
Hattori
Y
Y
Department of Endocrinology, Dokkyo University School of Medicine, Mibu, Japan. yhattori@dokkyomed.ac.jp
Banba
N
N
Gross
S S
SS
Kasai
K
K
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D017127:Glycation End Products, Advanced; D007372:Interferons / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000032:analysis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D000093423:Glycated Serum Albumin
D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D009573:Nitrites; D012333:RNA, Messenger; D012709:Serum Albumin; D009569:Nitric Oxide; D007372:Interferons; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D000093423:Glycated Serum Albumin