Activation of mitogen-activated protein kinases by arachidonic acid and its metabolites in vascular smooth muscle cells.

G N Rao,A S Baas,W C Glasgow,T E Eling,M S Runge,R W Alexander

doi:10.1016/s0021-9258(18)31674-0

Abstract

Previous studies from this laboratory and others suggest that arachidonic acid and its metabolites play important roles in a variety of biological processes such as signal transduction, contraction, chemotaxis, and cell growth and differentiation. Here we studied the effect of arachidonic 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 (NDGA), a potent inhibitor of the lipoxygenase system, significantly blocked the arachidonic acid-induced activation of MAP kinases, whereas indomethacin, an inhibitor of cyclooxygenase, had no effect. In VSMC, arachidonic acid was converted to 15-hydroxyeicosatetraenoic acid (15-HETE); NDGA inhibited the formation of this HETE. Exogenous addition of 15-HETE to VSMC caused stimulation of MAP kinases. Depletion of protein 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-lipoxygenase product of arachidonic acid, at least in part, mediates the arachidonic acid effect on MAP kinases; and 3) protein kinase C appears to be important in arachidonic acid activation of MAP kinases. Therefore, MAP kinases may play an important role in arachidonic acid signaling of VSMC growth and function.

Highlights

MAP kinases in VSMC; 2) 15-hydroxyeicosatetraenoic acid (15-HETE), a 15-lipoxygenase The MAP kinasekinase is a substrate for Raf-1, a serine/
To understand thesignal transduction events underlyingthe arachidonic acid-induced growth-related activities in VSMC, we examined its effect on MAP kinases
Understanding that MAP kinases are activated by arachidonic acid may strengthen the notion that thisfatty acid and itsmetabolites play an important role in the regulation ofVSMC growth

Summary

Introduction

MAP kinases in VSMC; 2) 15-HETE, a 15-lipoxygenase The MAP kinasekinase is a substrate for Raf-1, a serine/. To understand thesignal transduction events underlyingthe arachidonic acid-induced growth-related activities in VSMC, we examined its effect on MAP kinases. This suggests that metabolism of arachidonic acid through the cyclooxygenase or lipoxygenasepathways may be prerequisite for its effecton MAP kinase activation in VSMC.

Results

Conclusion