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(Hypertension. 1999;34:1259.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Salicylate Inhibition of Extracellular Signal-Regulated Kinases and Inducible Nitric Oxide Synthase

Zhongyan Wang; Peter Brecher

From the Whitaker Cardiovascular Institute and Department of Biochemistry, Boston University School of Medicine, Boston, Mass.

Correspondence to Peter Brecher, PhD, Boston University School of Medicine, 715 Albany St, Boston, MA 02118. E-mail pbrecher{at}bu.edu

Abstract—The expression of inducible nitric oxide synthase (iNOS) is a characteristic response to inflammation and can be inhibited with sodium salicylate. We used the cytokine-induced iNOS induction in cardiac fibroblasts as a model system in which to test the hypothesis that effects on mitogen-activated protein kinases (MAPKs) may explain the mechanism by which salicylate exerts its anti-inflammatory effects. Tumor necrosis factor- (TNF-) alone can induce extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase activity in a rapid and transient manner, whereas interferon- (IFN-) can induce only ERK. The inhibition of either the ERK pathway or p38 MAPK activity with selective inhibitors blocked cytokine-induced iNOS protein and nitrite production. Salicylate treatment inhibited iNOS expression induced by TNF- and IFN- and attenuated the phosphorylation of ERK by TNF- and IFN- either alone or in combination. Salicylate had no obvious effect on the activation of p38 MAPK or c-Jun N-terminal kinase. The results showed that salicylate inhibited the phosphorylation of ERK and iNOS expression induced by cytokines in a dose-dependent manner and suggested that salicylate exerts its anti-inflammatory action in part through inhibition of the ERK pathway and iNOS induction.

Key Words: inflammation • nitric oxide synthase • protein kinases • fibroblasts

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