Published online before print November 2, 2006, doi: 10.1161/01.ATV.0000251500.94478.18
© 2007 American Heart Association, Inc.
Vascular Biology |
Nox4 Is Required for Maintenance of the Differentiated Vascular Smooth Muscle Cell Phenotype
From the Department of Medicine, Division of Cardiology, Emory University, Atlanta, Ga.
Correspondence to Kathy K. Griendling, Emory University, Division of Cardiology, 319 WMB, 1639 Pierce Dr, Atlanta, GA 30322. E-mail kgriend{at}emory.edu
Objective— The mechanisms responsible for maintaining the differentiated phenotype of adult vascular smooth muscle cells (VSMCs) are incompletely understood. Reactive oxygen species (ROS) have been implicated in VSMC differentiation, but the responsible sources are unknown. In this study, we investigated the role of Nox1 and Nox4-derived ROS in this process.
Methods and Results— Primary VSMCs were used to study the relationship between Nox homologues and differentiation markers such as smooth muscle 
-actin (SM -actin), smooth muscle myosin heavy chain (SM-MHC), heavy caldesmon, and calponin. We found that Nox4 and differentiation marker genes were downregulated from passage 1 to passage 6 to 12, whereas Nox1 was gradually upregulated. Nox4 co-localized with SM -actin–based stress fibers in differentiated VSMC, and moved into focal adhesions in de-differentiated cells. siRNA against nox4 reduced NADPH-driven superoxide production in serum-deprived VSMCs and downregulated SM- actin, SM-MHC, and calponin, as well as SM- actin stress fibers. Nox1 depletion did not decrease these parameters.
Conclusion— Nox4-derived ROS are critical to the maintenance of the differentiated phenotype of VSMCs. These findings highlight the importance of identifying the specific source of ROS involved in particular cellular functions when designing therapeutic interventions.
The mechanisms responsible for maintaining the differentiated phenotype of adult vascular smooth muscle cells (VSMCs) are incompletely understood. Reactive oxygen species (ROS) have been implicated in VSMC differentiation, but the responsible sources are unknown. In this study, we investigated the role of Nox1 and Nox4-derived ROS in this process.
Key Words: reactive oxygen species • vascular smooth muscle • differentiation • gene expression
Related Article:
Arterioscler. Thromb. Vasc. Biol. 2007 27: 12-14.
This article has been cited by other articles:
 |
|
 |
|
  M. Y. Lee, A. S. Martin, P. K. Mehta, A. E. Dikalova, A. M. Garrido, S. R. Datla, E. Lyons, K.-H. Krause, B. Banfi, J. D. Lambeth, et al. Mechanisms of Vascular Smooth Muscle NADPH Oxidase 1 (Nox1) Contribution to Injury-Induced Neointimal Formation Arterioscler. Thromb. Vasc. Biol., April 1, 2009; 29(4): 480 - 487. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Xiao, Z. Luo, A. E. Pepe, A. Margariti, L. Zeng, and Q. Xu Embryonic stem cell differentiation into smooth muscle cells is mediated by Nox4-produced H2O2 Am J Physiol Cell Physiol, April 1, 2009; 296(4): C711 - C723. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Basuroy, S. Bhattacharya, C. W. Leffler, and H. Parfenova Nox4 NADPH oxidase mediates oxidative stress and apoptosis caused by TNF-{alpha} in cerebral vascular endothelial cells Am J Physiol Cell Physiol, March 1, 2009; 296(3): C422 - C432. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Schroder, K. Wandzioch, I. Helmcke, and R. P. Brandes Nox4 Acts as a Switch Between Differentiation and Proliferation in Preadipocytes Arterioscler. Thromb. Vasc. Biol., February 1, 2009; 29(2): 239 - 245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. N. Lavrentyev and K. U. Malik High glucose-induced Nox1-derived superoxides downregulate PKC-{beta}II, which subsequently decreases ACE2 expression and ANG(1-7) formation in rat VSMCs Am J Physiol Heart Circ Physiol, January 1, 2009; 296(1): H106 - H118. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. von Lohneysen, D. Noack, A. J. Jesaitis, M. C. Dinauer, and U. G. Knaus Mutational Analysis Reveals Distinct Features of the Nox4-p22phox Complex J. Biol. Chem., December 12, 2008; 283(50): 35273 - 35282. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Chen, M. T. Kirber, H. Xiao, Y. Yang, and J. F. Keaney Jr. Regulation of ROS signal transduction by NADPH oxidase 4 localization J. Cell Biol., October 22, 2008; 181(7): 1129 - 1139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Anilkumar, R. Weber, M. Zhang, A. Brewer, and A. M. Shah Nox4 and Nox2 NADPH Oxidases Mediate Distinct Cellular Redox Signaling Responses to Agonist Stimulation Arterioscler. Thromb. Vasc. Biol., July 1, 2008; 28(7): 1347 - 1354. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Wu, O. Platoshyn, A. L. Firth, and J. X.-J. Yuan Hypoxia divergently regulates production of reactive oxygen species in human pulmonary and coronary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, October 1, 2007; 293(4): L952 - L959. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Mittal, M. Roth, P. Konig, S. Hofmann, E. Dony, P. Goyal, A.-C. Selbitz, R. T. Schermuly, H. A. Ghofrani, G. Kwapiszewska, et al. Hypoxia-Dependent Regulation of Nonphagocytic NADPH Oxidase Subunit NOX4 in the Pulmonary Vasculature Circ. Res., August 3, 2007; 101(3): 258 - 267. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Schroder, I. Helmcke, K. Palfi, K.-H. Krause, R. Busse, and R. P. Brandes Nox1 Mediates Basic Fibroblast Growth Factor-Induced Migration of Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., August 1, 2007; 27(8): 1736 - 1743. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Deliri and C. A. McNamara Nox 4 Regulation of Vascular Smooth Muscle Cell Differentiation Marker Gene Expression Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 12 - 14. [Full Text] [PDF]
|
|