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

Abstract

1 The e ect of docosahexaenoic acid (DHA) on nitric oxide (NO) production and inducible NO synthase (iNOS) expression induced by interleukin (IL)-1b, and whether the e ect of DHA is related to its e ect on mitogen-activated protein kinase (MAPK) activation were investigated in cultured rat vascular smooth muscle cells (VSMCs). 2 DHA and eicosapentaenoic acid (EPA), although less potent, increased the NO production induced by IL-1b (3 ng ml 71 ) in a concentration-dependent manner (3 ± 30 mM) Arachidonic acid had no signi®cant e ect. The stimulatory e ect of DHA (30 mM) on the NO production was more obvious at lower concentrations of IL-1b. 3 IL-1b induced iNOS protein and mRNA expressions, which were signi®cantly potentiated by DHA. EPA (30 mM) had a tendency to increase the iNOS protein and mRNA expressions, but arachidonic acid had no e ect. 4 IL-1b-induced iNOS protein expression was signi®cantly inhibited by PD 98059 (10 mM), a selective inhibitor of p44/42 MAPK kinase, both in the absence and the presence of DHA. SB 203580 (10 mM), a selective inhibitor of p38 MAPK activity, had no signi®cant e ect, although had a tendency to inhibit slightly. 5 IL-1b increased the phosphorylation of p44/42 MAPK, while it did not apparently increase the phosphorylation of p38 MAPK. DHA signi®cantly potentiated the IL-1b-induced phosphorylation of p44/42 MAPK, while it had no signi®cant e ect on the phosphorylation of p38 MAPK. 6 These results suggest that DHA increases NO production by potentiating iNOS expression induced by IL-1b through mechanism involving p44/42 MAPK signalling cascade in rat VSMCs. The present study may contribute to the understanding of basic mechanisms underlying the bene®cial e ects of DHA on various cardiovascular disorders.

Docosahexaenoic Acid Enhances Cyclooxygenase-2 Induction by Facilitating p44/42, but Not p38, Mitogen-Activated Protein Kinase Activation in Rat Vascular Smooth Muscle Cells

“…COX-2 expression is dependent on the prolonged activation of p44 / 42 MAPK and the subsequent activation of nuclear factor-κB (5). We previously demonstrated that DHA enhanced the transient IL-1β-induced activation of p44 / 42 MAPK (7). The present study demonstrated that DHA also enhanced the prolonged activation of p44 / 42 MAPK, while it had no effect on the p38 MAPK activation.…”

“…However, highly conflicting results were obtained: both enhancement (12) and inhibition (13) of COX-2 induction have been reported. Similarly, both enhancement (7,14) and inhibition (13) of p44 / 42 or p38 MAPK have been reported. Reasons for these discrepancies are currently unclear, but may be explained by cell type-or stimulusspecific signaling mechanisms involved in the COX-2 induction or by experimental conditions such as concentration and applied form of fatty acids.…”

“…Protein expression was evaluated by Western blotting and densitometic analysis as described previously (7). COX-1 and COX-2 proteins were detected with COX-1 and COX-2 polyclonal rabbit antiserum (Cayman Chemical, Ann Arbor, MI, USA), respectively.…”

Recombinant interleukin-1ß dilates steelhead trout coronary microvessels: effect of temperature and role of the endothelium, nitric oxide and prostaglandins

“…There is evidence that IL-1β induces the production and/or release of vasoactive substances such as prostaglandins (PGs) and nitric oxide (NO) from mammalian vascular cells (Rossi et al, 1985;Hirafuji et al, 2002;Proescholdt et al, 2002;Schiltz and Sawchenko, 2002;Jedrzejowska-Szypulka et al, 2009). However, the results of experiments investigating the role of these two biological agents in modulating vascular resistance have been quite variable.…”

Nutrients: the environmental regulation of cardiovascular gene expression

“…Endothelium-independent mechanisms of x-3 PUFAs are essentially based on the maintenance of low intracellular Ca 2+ concentration in vascular smooth muscle cells (VSMCs) in order to reduce vasoconstriction [13]. Moreover, the x-3 PUFAs-induced NO increase in endothelial cells can significantly reduce platelet aggregation, leukocyte adhesion and VSMC proliferation and migration [4,12,22]. This action is carried out by modulating the platelet-derived growth factor (PDGF) transduction pathway [56] or the cyclin-dependent kinase-2 activity [47].…”