ROLE OF HYDROPEROXYEICOSATETRAENOIC ACIDS IN OXIDATIVE STRESS-INDUCEDACTIVATING PROTEIN-1 (AP-1) ACTIVITY

We have previously reported that hydrogen peroxide, an active oxygen s pecies and a cellular oxidant, induces c-Fos and c-Jun mRNA expression and DNA synthesis in vascular smooth muscle cells and that these even ts require arachidonic acid release and metabolism through the lipoxyg enase pathway. Here we have identified the eicosanoids that mediate th e hydrogen peroxide-induced growth-related events in these cells. Hydr ogen peroxide stimulated the production of 12- and 15-hydroperoxyeicos atetraenoic acids in vascular smooth muscle cells, Both 12- and 15-hyd roperoxyeicosatetraenoic acids induced the expression of c-Fos and c-J un protein and increased activating protein 1 (AP-1) activity, as meas ured by AP-1-DNA binding and AP-1-dependent human collagenase promoter -driven chloramphenicol acetyltransferase reporter gene transcription. Hydrogen peroxide and arachidonic acid also induced the expression of c-Fos and c-dun protein and AP-1 activity, Nordihydroguaiaretic acid, an inhibitor of the lipoxygenase pathway, significantly inhibited bot h hydrogen peroxide and arachidonic acid-stimulated c-Fos and c-Jun pr otein expression and AP-1 activity. Together, these findings suggest t hat hydrogen peroxide induces the production of eicosanoids and that t he eicosanoids are potential mediators of the oxidative stress-stimula ted growth-related events in vascular smooth muscle cells.