201. Hydrogen peroxide stimulates transcription of c-jun in vascular smooth muscle cells: role of arachidonic acid.
- Author
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Rao GN, Lassègue B, Griendling KK, and Alexander RW
- Subjects
- Animals, Cells, Cultured, Down-Regulation, Glyceraldehyde-3-Phosphate Dehydrogenases metabolism, Male, Masoprocol pharmacology, Peptide Fragments metabolism, Phospholipases A pharmacology, Phospholipases A2, Protein Kinase C metabolism, Quinacrine pharmacology, Rats, Rats, Sprague-Dawley, Arachidonic Acid pharmacology, Hydrogen Peroxide pharmacology, Muscle, Smooth, Vascular metabolism, Proto-Oncogene Proteins c-jun metabolism, RNA, Messenger metabolism, Transcription, Genetic drug effects
- Abstract
We reported previously that hydrogen peroxide induces DNA synthesis in rat aortic smooth muscle (RASM) cells. In the present paper we studied the mechanism by which hydrogen peroxide induces c-jun mRNA, an early response gene whose activation is required for mitogen-stimulated cell growth. Hydrogen peroxide induced c-jun mRNA in growth-arrested RASM cells in a time dependent manner. This stimulation was significantly inhibited by mepacrine, a phospholipase A2 (PLA2) inhibitor. Arachidonic acid, a PLA2 product, also increased c-jun mRNA with a time course similar to that of hydrogen peroxide. The increases in c-jun mRNA induced by hydrogen peroxide and arachidonic acid were significantly reduced (55%) by down-regulation of protein kinase C with a phorbol ester. Furthermore, the effect of hydrogen peroxide on c-jun mRNA was also reduced by NDGA, an inhibitor of the lipoxygenase-cytochrome P450 mono-oxygenase system, suggesting that metabolism of arachidonic acid through this pathway is required for the induction of c-jun mRNA by oxidants. Both hydrogen peroxide and arachidonic acid significantly increased c-jun transcription as demonstrated by nuclear run-on assays. Together these observations suggest that: (1) the induction of c-jun mRNA by hydrogen peroxide is mediated by PLA2-dependent arachidonic acid release and metabolism through the lipoxygenase-cytochrome P450 mono-oxygenase system; (2) PKC appears to be involved in this signaling pathway and (3) the induction of c-jun mRNA by hydrogen peroxide in RASM cells is due to increased transcription.
- Published
- 1993