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(Hypertension. 2008;52:143.)
© 2008 American Heart Association, Inc.

Original Articles

Nox4 Oxidase Overexpression Specifically Decreases Endogenous Nox4 mRNA and Inhibits Angiotensin II–Induced Adventitial Myofibroblast Migration

Mounir J. Haurani; M. Eugenia Cifuentes; Alexander D. Shepard; Patrick J. Pagano

From the Department of General Surgery (M.J.H., A.D.S.) and Hypertension and Vascular Research Division (M.E.C., P.J.P.), Henry Ford Health System, Detroit, Mich.

Correspondence to Patrick J. Pagano, Hypertension and Vascular Research Division, Room 7044, E&R Building, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202-2689. E-mail ppagano1{at}hfhs.org

The vascular adventitia is emerging as an important modulator of vessel remodeling. Adventitial myofibroblasts migrate to the neointima after balloon angioplasty, contributing to restenosis. We postulated that angiotensin II (Ang II) enhances adventitial myofibroblast migration in vitro via reduced nicotinamide-adenine dinucleotide phosphate oxidase–derived H₂O₂ and that Nox4-based oxidase promotes migration. Ang II increased myofibroblast migration in a concentration-dependent manner, with a peak increase of 1023±83%. Rat adventitial myofibroblasts were cotransfected with human Nox4 and human p22-phox plasmids or an empty vector. PCR showed an 8-fold increase in human Nox4 and human p22-phox plasmid expression. Using RT-PCR with primers specifically designed for rat reduced nicotinamide-adenine dinucleotide phosphate oxidases, endogenous Nox levels were determined. Ang II decreased endogenous Nox4 and Nox1 mRNA to 41% and 27% of control, respectively, but had no effect on Nox2. Cotransfection with human Nox4 and human p22-phox plasmids combined with Ang II reduced endogenous Nox4 mRNA levels (37±5% of control; P<0.05), whereas it had no significant effect on Nox1 or Nox2. In empty vector–transfected cells, Ang II increased myofibroblast migration by 192±32% versus vehicle (P<0.01) while increasing H₂O₂ (473±22% versus control; P<0.001). Cotransfection with human Nox4 and human p22-phox plasmids decreased Ang II-induced migration (46±6%; P<0.001) in parallel with attenuation of H₂O₂ production (23±8% versus empty vector; P<0.05). Our data suggest that Nox4 promotes Ang II-induced myofibroblast migration via an H₂O₂-dependent pathway. The data also suggest that Nox4 causes feedback inhibition of its own expression in adventitial myofibroblasts.

Key Words: adventitia • fibroblasts • myofibroblasts • migration • neointima • restenosis • NADPH oxidase

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