© 2001 American Heart Association, Inc.
Vascular Biology |
Enhanced Superoxide Production in Experimental Venous Bypass Graft Intimal Hyperplasia
Role of NAD(P)H Oxidase
From the Departments of Cardiovascular Medicine (N.E.J.W., T.J.G., K.M.C.) and Cardiothoracic Surgery (E.B.), University of Oxford, John Radcliffe Hospital, Oxford, UK.
Correspondence to Dr Keith Channon, Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK. E-mail keith.channon{at}cardiov.ox.ac.uk
Abstract—Vein graft intimal hyperplasia, due to smooth muscle cell (SMC) proliferation, remains a limiting factor in long-term vein graft patency. Increased superoxide production regulates SMC mitogenesis and contributes to reduced NO bioactivity in systemic models of vascular disease. We compared superoxide production in experimental venous bypass grafts with ungrafted veins and determined its enzymatic sources and cellular localization. Vascular superoxide production was measured in vein grafts and control jugular veins obtained from normocholesterolemic rabbits undergoing jugular vein–carotid artery interposition bypass grafting. Surgical isolation of the contralateral jugular vein, without bypass grafting, provided an additional control for the effects of surgical manipulation. Superoxide production was increased 3-fold in vein grafts compared with control veins. Systematic stimulation and inhibition of specific oxidases revealed that the major source of increased vein graft superoxide production was a membrane-associated NAD(P)H-dependent oxidase. Western blotting of vascular homogenates demonstrated corresponding increases in NAD(P)H oxidase p22phox (membrane-associated) and p67phox (cytosolic) subunits in vein grafts compared with jugular veins. There was marked intimal hyperplasia in vein grafts, and immunohistochemical staining of vessel cryosections revealed increased p22phox-expressing cells in vein grafts that were predominantly intimal SMCs. Superoxide generation is increased in experimental vein grafts compared with ungrafted veins. The principal source of increased superoxide generation in vein grafts is an NAD(P)H oxidase, expressed by intimal SMCs. These findings suggest a role for NAD(P)H oxidase–mediated superoxide production in the proliferative response to vascular injury in vein grafts.
Key Words: atherosclerosis • vein grafts • superoxide • vascular smooth muscles
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]
|
|
|
|
 |
|
 Z. A. Ali, C. A. Bursill, G. Douglas, E. McNeill, M. Papaspyridonos, A. L. Tatham, J. K. Bendall, A. M. Akhtar, N. J. Alp, D. R. Greaves, et al. CCR2-Mediated Antiinflammatory Effects of Endothelial Tetrahydrobiopterin Inhibit Vascular Injury-Induced Accelerated Atherosclerosis Circulation, September 30, 2008; 118(14_suppl_1): S71 - S77. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-J. Sung, A. Yee, S. G. Eskin, and L. V. McIntire Cyclic strain and motion control produce opposite oxidative responses in two human endothelial cell types Am J Physiol Cell Physiol, July 1, 2007; 293(1): C87 - C94. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Bendall, R. Rinze, D. Adlam, A. L. Tatham, J. de Bono, and K. M. Channon Endothelial Nox2 Overexpression Potentiates Vascular Oxidative Stress and Hemodynamic Response to Angiotensin II: Studies in Endothelial-Targeted Nox2 Transgenic Mice Circ. Res., April 13, 2007; 100(7): 1016 - 1025. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Lehoux Redox signalling in vascular responses to shear and stretch Cardiovasc Res, July 15, 2006; 71(2): 269 - 279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Qamirani, Y. Ren, L. Kuo, and T. W. Hein C-Reactive Protein Inhibits Endothelium-Dependent NO-Mediated Dilation in Coronary Arterioles by Activating p38 Kinase and NAD(P)H Oxidase Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 995 - 1001. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Ergul, J. S. Johansen, C. Stromhaug, A. K. Harris, J. Hutchinson, A. Tawfik, A. Rahimi, E. Rhim, B. Wells, R. W. Caldwell, et al. Vascular Dysfunction of Venous Bypass Conduits Is Mediated by Reactive Oxygen Species in Diabetes: Role of Endothelin-1 J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 70 - 77. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. M. Dourron, G. M. Jacobson, J. L. Park, J. Liu, D. J. Reddy, M. L. Scheel, and P. J. Pagano Perivascular gene transfer of NADPH oxidase inhibitor suppresses angioplasty-induced neointimal proliferation of rat carotid artery Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H946 - H953. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Guzik, J. Sadowski, B. Kapelak, A. Jopek, P. Rudzinski, R. Pillai, R. Korbut, and K. M. Channon Systemic Regulation of Vascular NAD(P)H Oxidase Activity and Nox Isoform Expression in Human Arteries and Veins Arterioscler Thromb Vasc Biol, September 1, 2004; 24(9): 1614 - 1620. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Cornelissen, J. Armstrong, and C. M. Holt Mechanical Stretch Induces Phosphorylation of p38-MAPK and Apoptosis in Human Saphenous Vein Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 451 - 456. [Abstract] [Full Text]
|
|
|
|
 |
|
 B. Lassegue and R. E. Clempus Vascular NAD(P)H oxidases: specific features, expression, and regulation Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R277 - R297. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Agarwal and M. S. Segal Intimal Exuberance: Veins in Jeopardy Am. J. Pathol., June 1, 2003; 162(6): 1759 - 1761. [Full Text] [PDF]
|
|
|
|
|
|
G. M. Jacobson, H. M. Dourron, J. Liu, O. A. Carretero, D. J. Reddy, T. Andrzejewski, and P. J. Pagano Novel NAD(P)H Oxidase Inhibitor Suppresses Angioplasty-Induced Superoxide and Neointimal Hyperplasia of Rat Carotid Artery Circ. Res., April 4, 2003; 92(6): 637 - 643. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. E. Rey and P. J. Pagano The Reactive Adventitia: Fibroblast Oxidase in Vascular Function Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 1962 - 1971. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Channon Oxidative Stress and Coronary Plaque Stability Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1751 - 1752. [Full Text] [PDF]
|
|
|
|
|
|
M. O. Laukkanen, A. Kivela, T. Rissanen, J. Rutanen, M. K. Karkkainen, O. Leppanen, J. H. Brasen, and S. Yla-Herttuala Adenovirus-Mediated Extracellular Superoxide Dismutase Gene Therapy Reduces Neointima Formation in Balloon-Denuded Rabbit Aorta Circulation, October 8, 2002; 106(15): 1999 - 2003. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Absood, A. Furutani, T. Kawamura, and L. M. Graham Differential PDGF secretion by graft and aortic SMC in response to oxidized LDL Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H725 - H732. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Itoh, S. Umemoto, M. Hiromoto, Y. Toma, Y. Tomochika, S. Aoyagi, M. Tanaka, T. Fujii, and M. Matsuzaki Importance of NAD(P)H Oxidase-Mediated Oxidative Stress and Contractile Type Smooth Muscle Myosin Heavy Chain SM2 at the Early Stage of Atherosclerosis Circulation, May 14, 2002; 105(19): 2288 - 2295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Mayr, M. Mayr, C. Li, F. Wernig, H. Dietrich, Y. Hu, and Q. Xu Loss of p53 Accelerates Neointimal Lesions of Vein Bypass Grafts in Mice Circ. Res., February 8, 2002; 90(2): 197 - 204. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. E.J. West, H. Qian, T. J. Guzik, E. Black, S. Cai, S. E. George, and K. M. Channon Nitric Oxide Synthase (nNOS) Gene Transfer Modifies Venous Bypass Graft Remodeling: Effects on Vascular Smooth Muscle Cell Differentiation and Superoxide Production Circulation, September 25, 2001; 104(13): 1526 - 1532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Pagano NAD(P)H Oxidase: Marker of the Dedifferentiated Neointimal Smooth Muscle Cell? Arterioscler Thromb Vasc Biol, February 1, 2001; 21(2): 175 - 177. [Full Text] [PDF]
|
|
|
|
|
|
U. Mayr, M. Mayr, C. Li, F. Wernig, H. Dietrich, Y. Hu, and Q. Xu Loss of p53 Accelerates Neointimal Lesions of Vein Bypass Grafts in Mice Circ. Res., February 8, 2002; 90(2): 197 - 204. [Abstract] [Full Text] [PDF]
|
|