Docosahexaenoic acid potentiates interleukin‐1β induction of nitric oxide synthase through mechanism involving p44/42 MAPK activation in rat vascular smooth muscle cells

• Published in: British journal of pharmacology 2002-06, Vol.136 (4), p.613-619
• Main Authors: Hirafuji, Masahiko, Machida, Takuji, Tsunoda, Marito, Miyamoto, Atsushi, Minami, Masaru
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; cardiovascular protection; Cardiovascular system; Docosahexaenoic acid; inducible nitric oxide synthase; Medical sciences; Miscellaneous; mitogen‐activated protein kinase; nitric oxide; Pharmacology. Drug treatments; vascular smooth muscle cells
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0704768

The effect of docosahexaenoic acid (DHA) on nitric oxide (NO) production and inducible NO synthase (iNOS) expression induced by interleukin (IL)‐1β, and whether the effect of DHA is related to its effect on mitogen‐activated protein kinase (MAPK) activation were investigated in cultured rat vascular smooth muscle cells (VSMCs). DHA and eicosapentaenoic acid (EPA), although less potent, increased the NO production induced by IL‐1β (3 ng ml−1) in a concentration‐dependent manner (3–30 μM) Arachidonic acid had no significant effect. The stimulatory effect of DHA (30 μM) on the NO production was more obvious at lower concentrations of IL‐1β. IL‐1β induced iNOS protein and mRNA expressions, which were significantly potentiated by DHA. EPA (30 μM) had a tendency to increase the iNOS protein and mRNA expressions, but arachidonic acid had no effect. IL‐1β‐induced iNOS protein expression was significantly inhibited by PD 98059 (10 μM), a selective inhibitor of p44/42 MAPK kinase, both in the absence and the presence of DHA. SB 203580 (10 μM), a selective inhibitor of p38 MAPK activity, had no significant effect, although had a tendency to inhibit slightly. IL‐1β increased the phosphorylation of p44/42 MAPK, while it did not apparently increase the phosphorylation of p38 MAPK. DHA significantly potentiated the IL‐1β‐induced phosphorylation of p44/42 MAPK, while it had no significant effect on the phosphorylation of p38 MAPK. These results suggest that DHA increases NO production by potentiating iNOS expression induced by IL‐1β through mechanism involving p44/42 MAPK signalling cascade in rat VSMCs. The present study may contribute to the understanding of basic mechanisms underlying the beneficial effects of DHA on various cardiovascular disorders. British Journal of Pharmacology (2002) 136, 613–619; doi:10.1038/sj.bjp.0704768