Targeting NAD(P)H Oxidase

Abstract

See related article, pages 985–994 Reactive Oxygen Species (ROS) have been shown to modulate vascular signaling in endothelium, smooth muscle, and adventitia, regulate vascular hypertrophy, inflammation, remodeling, intracellular calcium, and disturb nitric oxide bioactivity.1,2 Since Griendling et al discovered the activation of NAD(P)H oxidase by angiotensin II (Ang II),3 researches have focused on the regulation of this enzyme in Ang II signaling/Ang II-induced hypertension both in vitro and in vivo. Vascular NAD(P)H oxidase consists of multiple subunits including p22phox, p40phox, p47phox, p67phox, Rac1, and unique catalytic subunits, Nox isoforms (gp91phox homologue).4 The signaling mechanisms for the rapid activation of NAD(P)H oxidase by Ang II have been identified using cultured aortic vascular smooth muscle cells (VSMCs). Ang II rapidly activates PLC to increase intracellular calcium and diacylglycerol levels, which causes the activation of protein kinase C (PKC). PKC phosphorylates p47phox and releases ROS from Nox subunits. Subsequently, ROS activates cSrc, EGF-receptor, PI3-kinase, and Rac1, leading to the secondary activation of NAD(P)H oxidase to augment the intracellular ROS levels.4 These events occur within 30 minutes in cultured VSMCs. Considering the ROS generation associated with hypertension in vivo, the latter transcriptional upregulation of NAD(P)H oxidase subunits by Ang II might be more important. Ang II upregulates the expressions of NAD(P)H oxidase subunits after more than 4 hours including p22phox, Nox2 (gp91phox), p47phox, and p67phox,5 however the mechanisms of transcriptional regulations for NAD(P)H oxidase subunits have not fully been elucidated yet. In this issue of Circulation Research , Ni and colleagues identified that Ets-1 was a critical transcriptional regulator of p47phox induced by Ang II in vitro and in vivo.6 Ets-1 …