Mechanisms of vascular smooth muscle NADPH oxidase 1 (Nox1) contribution to injury-induced neointimal formation.
OBJECTIVE
Vascular NADPH oxidases (Noxes) have been implicated in cardiovascular diseases; however, the importance of individual Nox homologues remains unclear. Here, the role of the vascular smooth muscle cell (VSMC) Nox1 in neointima formation was studied using genetically modified animal models.


RESULTS
Wire injury-induced neointima formation in the femoral artery, along with proliferation and apoptosis, was reduced in Nox1(y/-) mice, but there was little difference in Tg(SMCnox1) mice compared with wild-type (WT) mice. Proliferation and migration were reduced in cultured Nox1(y/-) VSMCs and increased in Tg(SMCnox1) cells. Tg(SMCnox1) cells exhibited increased fibronectin secretion, but neither collagen I production nor cell adhesion was affected by alteration of Nox1. Using antibody microarray and Western blotting analysis, increased cofilin phosphorylation and mDia1 expression and decreased PAK1 expression were detected in Nox1(y/-) cells. Overexpression of S3A, a constitutively active cofilin mutant, partially recovered reduced migration of Nox1(y/-) cells, suggesting that reduction in cofilin activity contributes to impaired migration of Nox1(y/-) VSMCs.


CONCLUSIONS
These results indicate that Nox1 plays a critical role in neointima formation by mediating VSMC migration, proliferation, and extracellular matrix production, and that cofilin is a major effector of Nox1-mediated migration. Inhibition of Nox1 may be an efficient strategy to suppress neointimal formation.
Lee
Moo Yeol
MY
Emory University, Department of Medicine, Division of Cardiology, Atlanta, GA 30322, USA.
San Martin
Alejandra
A
Mehta
Puja K
PK
Dikalova
Anna E
AE
Garrido
Abel Martin
AM
Datla
S Raju
SR
Lyons
Erin
E
Krause
Karl-Heinz
KH
Banfi
Botond
B
Lambeth
J David
JD
Lassègue
Bernard
B
Griendling
Kathy K
KK
D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D051340:Cofilin 2 / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000201:enzymology / Q000293:injuries; D005353:Fibronectins / Q000378:metabolism; D000080865:Formins; D006965:Hyperplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000293:injuries / Q000473:pathology; D009247:NADH, NADPH Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D010766:Phosphorylation; D013997:Time Factors; D014162:Transfection; D017539:Tunica Intima / Q000201:enzymology* / Q000293:injuries / Q000473:pathology; D054462:p21-Activated Kinases / Q000378:metabolism
D002352:Carrier Proteins; C495816:Cfl2 protein, mouse; D051340:Cofilin 2; D024042:Collagen Type I; C491464:Diap1 protein, mouse; D005353:Fibronectins; D000080865:Formins; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases