(Hypertension. 1999;33:943-948.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Troglitazone Upregulates Nitric Oxide Synthesis in Vascular Smooth Muscle Cells
From the Department of Endocrinology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan.
Correspondence to Yoshiyuki Hattori, MD, Department of Endocrinology, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan. E-mail yhattori{at}dokkyomed.ac.jp
Abstract—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-1
(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-, or lipopolysaccharide with interferon-
(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-
B 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 -B–dependent. No expression of peroxisome
proliferator–activated receptor- (PPAR) was detected in
VSMC, and 15-deoxy-D12,14 prostaglandin
J2, the natural ligand for the PPAR, 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 PPAR-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.
Key Words: troglitazone • nitric oxide • peroxisome proliferator–activated receptor- • cytokines • muscle, smooth, vascular
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