Induction of mitogen-activated protein kinase phosphatase-1 by arachidonic acid 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, chemotaxis, and cell proliferation and differentiation. It was demonstrated recently that AA can activate mitogen-activated protein kinases (MAPKs), which are crucial for transducing signals initiating cell growth and apoptosis. Here 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 induction of MKP-1 mRNA and proteins in VSMCs in a time- and dose-dependent manner. Specific inhibitors of cyclooxygenase-, lipoxygenase-, and cytochrome P450-dependent metabolism did not affect AA-induced MKP-1 expression, indicating that eicosanoid biosynthesis was not involved in this process. The glutathione precursor N-acetylcysteine, an antioxidant, abolished AA-stimulated MKP-1 gene expression, whereas inhibition of protein kinase C by calphostin C had no influence on MKP-1 induction. VSMC pretreatment with genistein, a tyrosine kinase inhibitor, completely blocked AA-stimulated MKP-1 induction. MAPK kinase inhibitor PD 98059 did abolish AA-stimulated activation of extracellular signal-regulated kinases but not MKP-1 induction. Furthermore, agonists that increase AA release stimulated MKP-1 induction and activation of MAPKs, including extracellular signal-regulated kinases and c-Jun NH2-terminal protein kinases or stress-activated protein kinases. Taken together, our findings demonstrate that AA induced MKP-1 expression in VSMCs via activation of tyrosine kinases involving AA-induced free radical generation, suggesting an important role for MKP-1 in the regulation of AA-initiated signal transduction in VSMCs.
Metzler
B
B
Institute for Biomedical Aging Research, Austrian Academy of Sciences, A-6020 Innsbruck, Austria.
Hu
Y
Y
Sturm
G
G
Wick
G
G
Xu
Q
Q
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation; D004790:Enzyme Induction; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D010749:Phosphoprotein Phosphatases; D011493:Protein Kinase C / Q000378:metabolism; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis* / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013481:Superoxides / Q000378:metabolism
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D013481:Superoxides; D016718:Arachidonic Acid; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases