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Am J Physiol Cell Physiol 286: C1271-C1280, 2004. First published January 28, 2004; doi:10.1152/ajpcell.00143.2003
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VASCULAR BIOLOGY

Involvement of the mitogen-activated protein kinase cascade in peroxynitrite-mediated arachidonic acid release in vascular smooth muscle cells

Rita K. Upmacis, Ruba S. Deeb, Matthew J. Resnick, Rochelle Lindenbaum, Caryn Gamss, Dev Mittar, and David P. Hajjar

Departments of Biochemistry and Pathology, Center of Vascular Biology, Weill Medical College of Cornell University, New York, New York 10021

Submitted 10 April 2003 ; accepted in final form 22 January 2004

Eicosanoid production is reduced when the nitric oxide (NO·) pathway is inhibited or when the inducible NO synthase gene is deleted, indicating that the NO· and arachidonic acid pathways are linked. We hypothesized that peroxynitrite, formed by the reaction of NO· and superoxide anion, may cause signaling events leading to arachidonic acid release and subsequent eicosanoid generation. Western blot analysis of rat arterial smooth muscle cells demonstrated that peroxynitrite (100–500 µM) and 3-morpholinosydnonimine (SIN-1; 200 µM) stimulate phosphorylation of extracellular signal-regulated kinase (ERK), p38, and cytosolic phospholipase A2 (cPLA2). We found that peroxynitrite-induced arachidonic acid release was completely abrogated by the mitogen-activated protein/ERK kinase (MEK) inhibitor U0126 and by calcium chelators. With the p38 inhibitor SB-20219, we demonstrated that peroxynitrite-induced p38 phosphorylation led to minor arachidonic acid release, whereas U0126 completely blocked p38 phosphorylation. Addition of arachidonic acid caused p38 phosphorylation, suggesting that arachidonic acid or its metabolites are responsible for p38 activation. KN-93, a specific inhibitor of Ca2+/calmodulin-dependent kinase II (CaMKII), revealed no role for this kinase in peroxynitrite-induced arachidonic acid release in our cell system. Together, these results show that in response to peroxynitrite the cell initiates the MEK/ERK cascade leading to cPLA2 activation and arachidonic acid release. Thus studies investigating the role of the NO· pathway on eicosanoid production must consider the contribution of signaling pathways initiated by reactive nitrogen species. These findings may provide evidence for a new role of peroxynitrite as an important reactive nitrogen species in vascular disease.

reactive nitrogen species; prostaglandin H2 synthase; extracellular signal-regulated kinase; p38; cytosolic phospholipase A2


Address for reprint requests and other correspondence: R. K. Upmacis, Dept. of Pathology and Center of Vascular Biology, Rm. A626, Weill Medical College of Cornell Univ., 1300 York Ave., New York, NY 10021 (E-mail rupmacis{at}med.cornell.edu).




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