Vascular gp91 Beyond the Endothelium

present compelling evidence for conventional gp91containing NAD(P)H oxidase in the vascular endothelium and for the functional involvement of gp91 in endothelial cell NAD(P)H oxidase superoxide anion (O2) production and aberrant endothelium-dependent relaxation. Many studies have implicated reactive oxygen species in the impairment of endothelium-dependent vascular responses.2–10 Since their initial discovery in the vasculature and the suggestion of their importance in the modulation of endothelium-derived relaxing factor nitric oxide (EDRF/NO) bioactivity, phagocyte-like NAD(P)H oxidases have been under intense study in 3 major vascular cell types.11–18 Griendling et al19 showed the presence of angiotensin II (Ang II)–activatable NAD(P)H oxidase in rat vascular smooth muscle, and Mohazzab-H and colleagues12,14 also made seminal discoveries of endothelial and smooth muscle isotypes in bovine arteries. Because of the juxtaposition of these important sources of O2 near the sites of release and action of EDRF/NO, most interest in vascular biology has concerned components in these 2 cell types. Additional studies have demonstrated molecular evidence for most NAD(P)H oxidase components in both cell types,13,15,16,20 whereas there has been scant evidence for gp91 in vascular smooth muscle, although a homologue, mox1, has been suggested to stand in for gp91.21 In addition, my colleagues and I have shown that the vascular adventitia contains 4 phagocyte-like components, including gp91,9,10,18 and that rabbit adventitial fibroblasts contain an NAD(P)H oxidase functionally similar to the phagocyte oxidase.18 Recently, we screened a cDNA library prepared from these fibroblasts and obtained an 843-nucleotide base-pair coding region of neutrophil gp91 (amino acids 251 to 532 of neutrophil gp91) identical in sequence to rabbit leukocyte gp91 (K.A. Gauss, P.J. Pagano, M.T. Quinn, 2000, unpublished data), confirming the presence of this NAD(P)H oxidase component in aortic adventitial fibroblasts. Notwithstanding the importance of an endothelial isoform of this enzyme, there is substantial evidence that NAD(P)H oxidase components throughout the vascular wall are important contributors to the impairment of endothelium-dependent responses and the development of hypertension. Early studies suggested the importance of O2 in the vasculature of spontaneously hypertensive rats22 by showing that exogenous infusion of superoxide dismutase (SOD) could lower blood pressure. Beginning with the demonstration by Griendling et al19 of NAD(P)H oxidase activation by Ang II, important studies by this group showed that long-term Ang II infusion increases p22 mRNA concomitant with elevations in blood pressure and NAD(P)H oxidase-derived O2.4,23 Some studies have suggested that this induction occurs throughout the vascular wall.10,23 Recent evidence suggests that this regulation is particularly involved in forms of hypertension in which the renin-angiotensin system is activated,24,25 whereas catecholamine-induced hypertension does not increase O2 production by this oxidase system.7,23 The finding that Ang II causes vascular smooth muscle cell hypertrophy26,27 via activation of NAD(P)H oxidase15,19,28 has led to several studies examining other inducers of this response in smooth muscle cells, including platelet-derived growth factor and thrombin.29,30 Moreover, NAD(P)H oxidases are induced in fibroblasts by a number of factors, including tumor necrosis factor-a, interleukin-1, and transforming growth factor-b1. The demonstration that NAD(P)H oxidases are involved in mitogenic signaling in smooth muscle cells33–35 and fibroblasts36 implicated their relevance in atherosclerosis. Moreover, several studies have shown upregulation of O2-generating activity in hypercholesterolemia and atherosclerosis3,37 and the relevance of nonendothelial O2 sources in the impairment of endothelium-dependent responses in this disease state.38 p22 expression is increased across the vascular wall with the progression of atherosclerosis,39 and, in fact, a polymorphism of the p22 gene has been associated with coronary artery disease.40 However, Hsich et al41 recently demonstrated that knockout of the p47 gene does not affect the progression of atherosclerosis. Hence, these data support the involvement of the smooth muscle isozyme in this process, which does not seem to require p47.21 Because the study by Hsich et al41 examined the role of p47 in atherosclerosis only under normotensive conditions, it will be important to determine whether p47 can play a role in atherosclerosis under hypertensive conditions in which Ang II is elevated. There has been very little work addressing the contribution of NAD(P)H oxidases in the various vascular segments, particularly in endothelium-dependent responses. The study by Görlach et al1 begins to delineate a specific role for the endothelial isoform of NAD(P)H oxidase in impairment of endothelium-dependent relaxation. For example, the authors The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Hypertension & Vascular Research Division, Henry Ford Hospital, Detroit, Mich. Correspondence to Patrick J. Pagano, E & R Building, Room 7044, Hypertension & Vascular Research Division, Henry Ford Hospital, 2799 Grand Blvd, Detroit, MI 43202. E-mail [email protected] (Circ Res. 2000;87:1-3.) © 2000 American Heart Association, Inc.