No Superoxide—No Stress?

Abstract

NADPH oxidases of the Nox family are enzymes whose only known function is the production of reactive oxygen species (ROS). Since the first report on a vascular NADPH oxidase by Griendling et al in 1994,1 several thousand publications have been devoted to this topic. The general impression is that under physiological conditions, Nox proteins contribute to vascular signaling, whereas the overactivation and induction of NADPH oxidases promote vascular disease.2 See accompanying article on page 1368 In the vascular system, the NADPH oxidases Nox1, Nox2, Nox4, and Nox5 are expressed. Unlike the case with the other vascular Nox homologues, the activity of Nox4 appears to be predominantly controlled by its expression level, and proinflammatory mediators that induce Nox1 or Nox2 instead appear to suppress Nox4 expression.3 Nox4 is also the only vascular homolog that directly produces hydrogen peroxide (H2O2) and thus is incapable of scavenging nitric oxide (NO) or producing peroxynitrite (ONOO−).4 As a consequence of these unique properties, so far little consensus regarding the physiological function of Nox4 has been reached.3 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Ray et al report the generation and characterization of a transgenic mouse with endothelial-specific Nox4 overexpression.5 Vascular segments and endothelial cells of these animals had a significant increase in H2O2 generation that was sufficient to result in a substantial increase in the oxidation of peroxiredoxin 1. Despite these signs of increased protein oxidation, the blood pressure of the animals was lower under basal conditions and after angiotensin II treatment. Furthermore, endothelium-dependent relaxation was enhanced compared with wild-type animals. The latter effects were sensitive to catalase ex vivo and N -acetylcysteine in vivo, suggesting that they were mediated by H2 …