Transactivation of the EGF receptor and a PI3 kinase–ATF-1 pathway is involved in the upregulation of NOX1, a catalytic subunit of NADPH oxidase

AbstractWe previously reported that hypertrophy of vascular smooth muscle cells caused by prostaglandin (PG) F2α is mediated by the induction of NOX1, a catalytic subunit of NADPH oxidase that generates superoxide. The signal transduction pathway(s) involved in this process, however, remained unresolved. PGF2α enhanced the phosphorylation of the epidermal growth factor (EGF) receptor, and a selective inhibitor of EGF receptor kinase, tyrphostin AG1478, significantly suppressed PGF2α-induced NOX1 expression. AG1478 also blunted the PGF2α-induced phosphorylation of extracellular signal-regulated protein kinase (ERK)1/2 and Akt. Phosphoinositide 3 (PI3) kinase inhibitors not only reduced PGF2α-induced NOX1 expression, but also suppressed the phosphorylation of ATF-1, a transcription factor previously shown to play a key role in the induction of NOX1. Accordingly, the transactivation of the EGF receptor and the activation of ERK1/2, PI3 kinase, and ATF-1 constitute the signaling pathways involved in the upregulation of NOX1