PT  - JOURNAL ARTICLE
AU  - Takuji Machida
AU  - Yukihiro Hamaya
AU  - Sachiko Izumi
AU  - Yumika Hamaya
AU  - Kenji Iizuka
AU  - Yasuyuki Igarashi
AU  - Masaru Minami
AU  - Roberto Levi
AU  - Masahiko Hirafuji
TI  - Sphingosine 1-Phosphate Inhibits Nitric Oxide Production Induced by Interleukin-1β in Rat Vascular Smooth Muscle Cells
AID  - 10.1124/jpet.107.127290
DP  - 2008 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 200--209
VI  - 325
IP  - 1
4099  - http://jpet.aspetjournals.org/content/325/1/200.short
4100  - http://jpet.aspetjournals.org/content/325/1/200.full
SO  - J Pharmacol Exp Ther2008 Apr 01; 325
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics