ACTIVATION OF MITOGEN-ACTIVATED PROTEIN-KINASES BY ARACHIDONIC-ACID AND ITS METABOLITES IN VASCULAR SMOOTH-MUSCLE CELLS

Previous studies from this laboratory and others suggest that arachido nic acid and its metabolites play important roles in a variety of biol ogical processes such as signal transduction, contraction, chemotaxis, and cell growth and differentiation. Here we studied the effect of ar achidonic acid on mitogen-activated protein (MAP) kinases in vascular smooth muscle cells (VSMC). Arachidonic acid activated MAP kinases in VSMC in a time-and dose-dependent manner. Nordihydroguaiaretic acid (N DGA), a potent inhibitor of the Lipoxygenase system, significantly blo cked the arachidonic acid-induced activation of MAP kinases, whereas i ndomethacin, an inhibitor of cyclooxygenase, had no effect. In VSMC, a rachidonic acid was converted to 15-hydroxyeicosatetraenoic acid (15-H ETE); NDGA inhibited the formation of this HETE. Exogenous addition of 15-HETE to VSMC caused stimulation of MAP kinases. Depletion of prote in kinase C attenuated both the arachidonic acid- and 15-HETE-induced activation of MAP kinases in VSMC. Together these results suggest that 1) arachidonic acid activates MAP kinases in VSMC; 2) 15-HETE, a 15-l ipoxygenase product of arachidonic acid, at least in part, mediates th e arachidonic acid effect on MAP kinases; and 3) protein kinase C appe ars to be important in arachidonic acid activation of MAP kinases, The refore, MAP kinases may play an important role in arachidonic acid sig naling of VSMC growth and function.