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CARDIOVASCULAR

Sphingosine 1-Phosphate Inhibits Nitric Oxide Production Induced by Interleukin-1β in Rat Vascular Smooth Muscle Cells

Department of Pharmacology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan (T.M., Yuk.H., S.I., Yum.H., K.I., M.M., M.H.); Department of Biomembrane and Biofunctional Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, Japan (Y.I.); and Department of Pharmacology, Weill Cornell Medical College, New York, New York (R.L.)

Sphingosine 1-phosphate (S1P) is a lipid mediator that exerts potent and diverse biological effects on several cardiovascular cells. We investigated the effect of S1P on interleukin (IL)-1β-induced nitric oxide (NO) production and inducible NO synthase (iNOS) expression in rat vascular smooth muscle cells (VSMCs). S1P inhibited NO production at concentrations higher than 0.1 µM; this was associated with the inhibition of iNOS protein and mRNA expression. S1P also inhibited IL-1β-induced GTP cyclohydrolase I (GTPCH) mRNA expression. Pertussis toxin (PTX) partially attenuated the inhibitory effects of S1P on NO production and iNOS protein induction, whereas it completely blocked the inhibitory effects on iNOS and GTPCH mRNA expression. S1P inhibited iNOS expression in Ca²⁺-depleted conditions; PTX did not modify this effect. The Rho kinase inhibitor Y 27632 partially but significantly attenuated the inhibitory effect of S1P on iNOS expression in Ca²⁺-depleted condition but did not affect it in the presence of Ca²⁺. S1P significantly inhibited IL-1β-induced persistent activation of extracellular signal-regulated kinase (ERK) but had no effect in Ca²⁺-depleted conditions. Thus, S1P inhibits IL-1β induction of NO production and iNOS expression in rat VSMCs through multiple mechanisms involving both PTX-sensitive and -insensitive G proteins coupled to S1P receptors. Furthermore, Ca²⁺-dependent ERK inhibition and Ca²⁺-independent Rho kinase activation might be involved in the inhibitory mechanism of iNOS expression. Through its action on NO production by VSMCs, S1P may play an important role in the progression of local vascular injury associated with thrombosis, atherosclerosis, and hypertension.

Address correspondence to: Dr. Masahiko Hirafuji, Department of Pharmacology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan. E-mail: hirafuji{at}hoku-iryo-u.ac.jp