Troglitazone upregulates nitric oxide synthesis in vascular smooth muscle cells.
We investigated the effects of troglitazone on cytokine-stimulated nitric oxide (NO) production in cultured rat vascular smooth muscle cells (VSMC). The increase in NO formation caused by interleukin-1alpha (IL-1) was enhanced by troglitazone in a concentration-dependent manner. Bacterial lipopolysaccharide-stimulated NO synthesis was also increased by troglitazone. The combinations of IL-1, tumor necrosis factor-alpha, or lipopolysaccharide with interferon-gamma (IFN) were strong stimuli for induction of NO synthesis in VSMC, which were further potentiated by the presence of troglitazone. When troglitazone was added at increasing intervals after the stimulation of VSMC with IL-1, the enhancement in NO production decreased as the interval lengthened, suggesting that troglitazone alters NO synthase (NOS) expression by VSMC rather than having a direct affect on VSMC NOS activity. Troglitazone had no effect on IL-1-elicited or IL-1/IFN-elicited nuclear factor-kappaB activity in VSMC. Troglitazone inhibited the degradation of cytokine-induced NOS mRNA. Thus troglitazone appears to enhance IL-1-induced NOS mRNA levels by prolonging its half-life rather than activating its transcription, which is nuclear factor -kappaB-dependent. No expression of peroxisome proliferator-activated receptor-gamma (PPARgamma) was detected in VSMC, and 15-deoxy-D12,14 prostaglandin J2, the natural ligand for the PPARgamma, did not resemble the effect of troglitazone on IL-1-induced NO synthesis. These results indicate that troglitazone upregulates cytokine-stimulated NO synthesis in VSMC through PPARgamma-independent mechanisms. Considering its inhibitory effects on the action of numerous growth factors on VSMC, the direct vascular effects of troglitazone shown in this study may have important implications for prevention of restenosis and possibly atherosclerosis.
Hattori
Y
Y
Department of Endocrinology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan. yhattori@dokkyomed.ac.jp
Hattori
S
S
Kasai
K
K
D000818:Animals; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists* / Q000502:physiology; D000077288:Troglitazone; D015854:Up-Regulation
D002839:Chromans; D007375:Interleukin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D000077288:Troglitazone