Role of p22phox in angiotensin II and platelet-derived growth factor AA induced activator protein 1 activation in vascular smooth muscle cells.

Abstract

Reactive oxygen species (ROS) are involved in the transcriptional response to angiotensin (ANG) II. In this setting the role of NAD(P)H oxidase, an important source of ROS as second messengers, is not completely understood. In particular in human cells detailed insights into this mechanism are lacking. We investigated the role of ANG II and platelet-derived growth factor (PDGF) AA induced ROS generation derived from p22phox-containing NAD(P)H oxidase in the activation of activator protein (AP) 1 in human vascular smooth muscle cells (SMCs). Both ANG II and PDGF AA induced ROS generation in SMCs which was angiotensin type 1 receptor and PDGF alpha receptor dependent. Specific inhibition of the p22phox subunit of the NAD(P)H oxidase using either p22phox neutralizing antibody or p22phox antisense oligodeoxynucleotides (ODNs) attenuated both ANG II and PDGF AA induced ROS generation. Furthermore, PDGF AA but not ANG II induced p22phox mRNA expression. ANG II and PDGF AA both activated the redox-sensitive transcription factor AP-1, which was inhibited by p22phox antisense ODNs. These findings demonstrate that AP-1 activation in human SMCs in response to ANG II and PDGF AA is mediated via generation of p22phox-dependent ROS. This highlights the crucial role of the p22phox-containing NAD(P)H oxidase in the ANG II and PDGF AA induced signal transduction pathway.