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Inducible nitric oxide synthase contributes to MAPK‐phosphatase induction and abundance of cyclooxygenase‐2 expression in an inflammatory setting
Author(s) -
Lamon Brian David,
Upmacis Rita K.,
Deeb Ruba S.,
Hajjar David P.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.357.4
Subject(s) - nitric oxide synthase , p38 mitogen activated protein kinases , cyclooxygenase , nitric oxide , mapk/erk pathway , phosphatase , inflammation , downregulation and upregulation , chemistry , lipopolysaccharide , phosphorylation , endocrinology , medicine , biology , biochemistry , immunology , enzyme , gene
Cyclooxygenase (COX)‐2 and inducible nitric oxide synthase (iNOS) are responsive to inflammatory stimuli and have been localized to vascular smooth muscle cells (SMCs) in pathophysiological settings, e.g. atherosclerosis. Furthermore, the production of, and subsequent impact of COX products appear to be correlative with the status of NO synthesis and bioavailability. This study examined the role of inflammation‐driven NO synthesis on COX‐2 expression in rat aortic SMCs. Concurrent stimulation of quiescent SMCs with lipopolysaccharide (LPS) and interferon (IFN)‐γ induced iNOS and COX‐2 expression maximally at 2‐4hr. Inhibition of NO synthesis (LNMMA) significantly reduced nitrite (140±8 vs. 19±7 nmol/mg protein) and enhanced LPS+IFN‐γ‐mediated COX‐2 mRNA (156‐ vs. 43‐fold increase) and protein expression (5‐fold) at 30 and 60min. COX‐2 induction was associated with activation of the ERK, p38 and JNK pathways. Importantly, LNMMA enhanced ERK and p38 phosphorylation, and suppressed MAPK‐phosphatase (MKP)‐1 induction. Consistent with these data, exposure of SMCs from iNOS‐/‐ mice to LPS+IFN‐γ produced a more robust induction (p<0.05) of COX‐2 and a dramatically attenuated upregulation of MKP‐1 vs. WT. These findings provide pharmacological and genetic evidence implicating an inhibitory influence of iNOS‐derived species on phosphorylation cascades associated with COX‐2‐induction in SMCs.