Regulatory Peptides 91 (2000) 21–27 www.elsevier.com / locate / regpep Invited review q Reactive oxygen species as mediators of angiotensin II signaling * Kathy K. Griendling , Masuko Ushio-Fukai Division of Cardiology, School of Medicine, Emory University, 319 WMB, 1639 Pierce Drive, Atlanta, GA 30322, USA Received 10 May 2000; received in revised form 10 May 2000; accepted 24 May 2000 Abstract Angiotensin II stimulates a plethora of signaling pathways leading to cell growth and contraction. Recent work has shown that reactive oxygen species are involved in transducing many of the effects of angiotensin II, and are in fact produced in response to agonist-receptor binding. Angiotensin II stimulates a NAD(P)H oxidase to produce superoxide and hydrogen peroxide, both of which may act on intracellular growth-related proteins and enzymes to mediate the final physiological response. Of particular importance is hydrogen peroxide, which mediates angiotensin II stimulation of such important intracellular signals as EGF-receptor transactivation, p38 mitogen activated protein kinase, and Akt. Future work will be directed towards identifying other important redox-sensitive signaling pathways and their relationship to the physiology and pathophysiology of the renin–angiotensin system.  2000 Elsevier Science B.V. All rights reserved. Keywords: Angiotensin; Reactive oxygen species; Signal transduction; NADPH oxidase 1. Introduction 2. ROS Over the years, much insight has been gained into the ROS are molecules that are ultimately derived from biochemical pathways by which angiotensin II (Ang II) oxygen but have undergone univalent reduction, so that exerts its effects on cells. The cloning of the Ang II types they readily react with other biological products. ROS 2 1A, 1B and 2 receptors led the way for a more molecular include superoxide anion (O ? ), hydrogen peroxide 2 understanding of how Ang II interacts with vascular, renal (H O ), hydroxyl radical (OH ? ), nitric oxide (NO ? ), and 2 2 2 and neuronal cells to produce its myriad physiological peroxynitrite (OONO ? ). Of these, O ? and H O have 2 2 2 responses. Along with this breakthrough, a full characteri- been shown to be produced by Ang II [1,2] and to alter the zation of classical signaling through the phospholipase C, activity of specific signaling proteins and enzymes, or to calcium and protein kinase C pathways has been accom- serve as a rheostat that closely regulates the activity of a plished. In addition, the ability of Ang II to activate discrete set of biochemical reactions [3]. There have also tyrosine kinase pathways leading to cellular hypertrophy been a few reports of Ang II-induced NO ? production by and proliferation has been well established. One of the endothelial cells [4,5]. newest additions to this list of signaling pathways is the In order for ROS to serve a second messenger function, ability of Ang II to produce reactive oxygen species both the production and inactivation of ROS must be 2 (ROS), and the involvement of these molecules in trans- tightly regulated (Fig. 1). The half-life of O ? is quite 2 ducing some of the growth-related signals that are the short (seconds) both because of its inherent instability and hallmark of Ang II activation. the efficient antioxidant defenses of the cell. Dismutation 2 of O ? by superoxide dismutase (SOD) not only serves 2 2 to scavenge O ? , but it also produces the more stable q 2 Brief review: ‘‘100 Years of Renin’’ series. ROS H O . Catalase and glutathione peroxidase are two of 2 2 *Corresponding author. Tel.: 1 1-404-727-8386; fax: 1 1-404-727- the most important scavengers of hydrogen peroxide, in 3585. E-mail address: kgriend@emory.edu (K.K. Griendling). both cases converting it to water. 0167-0115 / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved. PII: S0167-0115(00)00136-1