Angiotensin II-stimulated vascular remodeling: the search for the culprit oxidase.

Hypertrophy and hyperplasia of vascular smooth muscle cells are hallmarks of the common vascular disorders of atherosclerosis, restenosis, and hypertension and contribute to their long-term sequelae. Angiotensin II (Ang II) is a potent smooth muscle mitogen and hypertrophic agent. The importance of Ang II in the pathogenesis of vascular disease is reflected in the efficacy of angiotensin-converting enzyme inhibitors and Ang II receptor blockers in the treatment of atherosclerosis and hypertension. Despite the widespread use of these agents in clinical practice, our understanding of the mechanisms through which Ang II exerts its effects on the vasculature is not complete. The studies by Lassègue et al1 and Wang et al2 in this issue of Circulation Research go a long way in elucidating the molecular basis for the effects of Ang II on vascular smooth muscle cell growth. To fully appreciate the significance of the reported findings, one has to place them into historical perspective. The role of oxidative stress in the pathogenesis of the above-mentioned vascular disorders has been well recognized for some time.3 It has come to light that humoral factors, such as Ang II, platelet-derived growth factor, and thrombin, directly lead to oxidative stress in smooth muscle cells via the generation of reactive oxygen species (ROS), which are essential for their mitogenic and hypertrophic properties.4 –7 With these findings in hand, investigators directed their efforts toward identifying the enzymatic source of growth factor–stimulated ROS in vascular smooth muscle cells. Attention was mainly focused on identifying an oxidase functionally analogous to the phagocyte NADPH oxidoreductase, because many but not all components of its multimolecular complex are expressed in vascular smooth muscle cells.7,8 However, attempts to show significant expression of the enzymatically active flavoprotein subunit gp91 of this oxidase in smooth muscle cells were unsuccessful. Therefore, the cloning of a homologous protein nox1 (NAD(P)H oxidase 1), originally termed mox-1 (mitogenic oxidase-1), from a colon cancer cell line, and also expressed to a lesser extent in rat vascular smooth muscle cells, was hailed as a significant breakthrough.9 Other gp91 homologues, expressed primarily in the kidney10 and thyroid,11 have also been identified recently. This brings us to the present study by Lassègue et al,1 demonstrating for the first time the importance of the newly discovered nox1 in Ang II–stimulated and plateletderived growth factor–stimulated short-term ROS generation and activation of the growth-promoting signaling proteins Akt and p38 mitogen-activated protein kinase in cultured rat smooth muscle cells. In the absence of specific means to inhibit nox1 activity, Lassègue et al use an adenovirus encoding antisense nox1 to suppress its expression. The study also suggests that transcriptional upregulation of nox1 by Ang II may be responsible for longerterm growth of smooth muscle cells induced by this mitogen. Standing alone, the study provides convincing evidence for the role of nox1 in mitogen-stimulated smooth muscle cell growth in vitro. However, on the basis of the methodology used, it would be fair to say that the data are not conclusive in this regard. Antisense, though effective at suppressing nox1 expression, may not be entirely specific. This leaves open the possibility, which is acknowledged by the authors, that another homologous oxidase, known or unknown, may also participate in mitogen-stimulated ROS generation and growth. The study by Wang et al,2 not coincidentally published in this same issue, seems to contradict the in vitro findings of Lassègue et al1 or at least question their physiological relevance. Using knockout mice, Wang et al2 prove that it is gp91, present primarily in endothelial cells and adventitial fibroblasts but also expressed to a much lesser degree in smooth muscle cells, that is chiefly responsible for Ang II–stimulated vascular oxidative stress and smooth muscle growth in vivo. This supports a previous report that Ang II stimulates ROS production in adventitial fibroblasts by inducing other components of the NADPH oxidase.12 Assuming for the moment that there is a mouse homologue of nox1 (one has yet to be cloned) and ignoring possible species-specific differences in the response to Ang II, there are at least two explanations for the seemingly contradictory findings embodied in these studies. The most straightforward one is that nox1 is not expressed in smooth muscle cells in vivo or that expressed nox1 plays a small role, if The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md. Correspondence to Kaikobad Irani, Ross 1023, The Johns Hopkins University School of Medicine, 720 Rutland Ave, Baltimore, MD 21205. E-mail [email protected] (Circ Res. 2001;88:858-860.) © 2001 American Heart Association, Inc.