Induction of mitogen-activated protein kinase phosphatase-1 by arachidonicacid in vascular smooth muscle cells

Arachidonic acid (AA) and its metabolites play important roles in a variety of biological processes, such as signal transduction, contraction, chemota xis, and cell proliferation and differentiation. It was demonstrated recent ly that AA can activate mitogen-activated protein kinases (MAPKs), which ar e crucial for transducing signals initiating cell growth and apoptosis. Her e we studied the effect of AA on the induction of MAPK phosphatase-1 (MKP-1 ) in vascular smooth muscle cells (VSMCs) and found that AA stimulated indu ction of MKP-1 mRNA and proteins in VSMCs in a time- and dose-dependent man ner. Specific inhibitors of cyclooxygenase-, lipoxygenase-, and cytochrome P450-dependent metabolism did not affect AA-induced MKP-1 expression, indic ating that eicosanoid biosynthesis was not involved in this process. The gl utathione precursor N-acetylcysteine, an antioxidant, abolished AA-stimulat ed MKP-1 gene expression, whereas inhibition of protein kinase C by calphos tin C had no influence on MKP-1 induction. VSMC pretreatment with genistein , a tyrosine kinase inhibitor, completely blocked AA-stimulated MKP-1 induc tion. MAPK kinase inhibitor PD 98059 did abolish AA-stimulated activation o f extracellular signal-regulated kinases but not MKP-1 induction. Furthermo re, agonists that increase AA release stimulated MKP-1 induction and activa tion of MAPKs, including extracellular signal-regulated kinases and c-Jun N H2-terminal protein kinases or stress-activated protein kinases, Taken toge ther, our findings demonstrate that AA induced MKP-1 expression in VSMCs vi a activation of tyrosine kinases involving AA-induced free radical generati on, suggesting an important role for MKP-1 in the regulation of AA-initiate d signal transduction in VSMCs.