This Article Full Text Full Text (PDF) All Versions of this Article: 26/9/2063    most recent 01.ATV.0000235694.69719.e2v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schepers, A. Articles by Quax, P.H.A. Search for Related Content PubMed PubMed Citation Articles by Schepers, A. Articles by Quax, P.H.A. Related Collections Restenosis Animal models of human disease Growth factors/cytokines Peripheral vascular disease Coagulation inhibitors Gene therapy Mechanism of atherosclerosis/growth factors

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2063.)
© 2006 American Heart Association, Inc.

Vascular Biology

Anti–MCP-1 Gene Therapy Inhibits Vascular Smooth Muscle Cells Proliferation and Attenuates Vein Graft Thickening Both In Vitro and In Vivo

A. Schepers; D. Eefting; P.I. Bonta; J.M. Grimbergen; M.R. de Vries; V. van Weel; C.J. de Vries; K. Egashira; J.H. van Bockel; P.H.A. Quax

From the Gaubius Laboratory TNO-Quality of Life (A.S., D.E., J.M.G., M.R.d.V., V.v.W., P.H.A.Q.), Leiden; the Department of Vascular Surgery (A.S., D.E., V.v.W., J.H.v.B., P.H.A.Q.), Leiden University Medical Centre, Leiden; and the Department of Medical Biochemistry (P.I.B., C.J.d.V.), Academic Medical Center, Amsterdam, The Netherlands; and the Graduate School of Medical Sciences (K.E.), Kyushu University, Fukuoka, Japan.

Correspondence to P.H.A. Quax, PhD, Gaubius Laboratory, TNO-Quality of Life, Department of Biomedical Research, Zernikedreef 9, 2301 CE, Leiden, The Netherlands. E-mail pha.quax{at}pg.tno.nl

Objective— Because late vein graft failure is caused by intimal hyperplasia (IH) and accelerated atherosclerosis, and these processes are thought to be inflammation driven, influx of monocytes is one of the first phenomena seen in IH, we would like to provide direct evidence for a role of the MCP-1 pathway in the development of vein graft disease.

Methods and Results— MCP-1 expression is demonstrated in various stages of vein graft disease in a murine model in which venous interpositions are placed in the carotid arteries of hypercholesterolemic ApoE3Leiden mice and in cultured human saphenous vein (HSV) segments in which IH occurs. The functional involvement of MCP-1 in vein graft remodeling is demonstrated by blocking the MCP-1 receptor CCR-2 using 7ND-MCP-1. 7ND-MCP1 gene transfer resulted in 51% reduction in IH in the mouse model, when compared with controls. In HSV cultures neointima formation was inhibited by 53%. In addition, we demonstrate a direct inhibitory effect of 7ND-MCP-1 on the proliferation of smooth muscle cell (SMC) in HSV cultures and in SMC cell cultures.

Conclusion— These data, for the first time, prove that MCP-1 has a pivotal role in vein graft thickening due to intimal hyperplasia and accelerated atherosclerosis.

Involvement of MCP-1 in vein graft intimal hyperplasia (IH) was studied. MCP-1 was detected by immunohistochemistry in murine vein grafts and cultured human saphenous veins. Functional involvement of MCP-1 was assessed by exposure to a MCP-1-antagonist. This reduced IH in both models and inhibited smooth muscle cell proliferation in vitro.

Key Words: vein graft disease • intimal hyperplasia • MCP-1 • smooth muscle cells • inflammation

This article has been cited by other articles:

				D. Strassheim, S. R. Riddle, D. L. Burke, M. W. Geraci, and K. R. Stenmark Prostacyclin Inhibits IFN-{gamma}-Stimulated Cytokine Expression by Reduced Recruitment of CBP/p300 to STAT1 in a SOCS-1-Independent Manner J. Immunol., December 1, 2009; 183(11): 6981 - 6988. [Abstract] [Full Text] [PDF]

				G. Grassia, M. Maddaluno, A. Guglielmotti, G. Mangano, G. Biondi, P. Maffia, and A. Ialenti The anti-inflammatory agent bindarit inhibits neointima formation in both rats and hyperlipidaemic mice Cardiovasc Res, December 1, 2009; 84(3): 485 - 493. [Abstract] [Full Text] [PDF]

				S. A. Parikh and M. A. Costa Secondary Prevention, the Interventional Way: Prophylactic Drug-Eluting Stents for Nonobstructive Saphenous Vein Graft Disease Circulation, November 17, 2009; 120(20): 1940 - 1942. [Full Text] [PDF]

				H. S. K. Potula, D. Wang, D. Van Quyen, N. K. Singh, V. Kundumani-Sridharan, M. Karpurapu, E. A. Park, W. C. Glasgow, and G. N. Rao Src-dependent STAT-3-mediated Expression of Monocyte Chemoattractant Protein-1 Is Required for 15(S)-Hydroxyeicosatetraenoic Acid-induced Vascular Smooth Muscle Cell Migration J. Biol. Chem., November 6, 2009; 284(45): 31142 - 31155. [Abstract] [Full Text] [PDF]

				T. Aoki, H. Kataoka, R. Ishibashi, K. Nozaki, K. Egashira, and N. Hashimoto Impact of Monocyte Chemoattractant Protein-1 Deficiency on Cerebral Aneurysm Formation Stroke, March 1, 2009; 40(3): 942 - 951. [Abstract] [Full Text] [PDF]

				F. Montecucco and F. Mach Common inflammatory mediators orchestrate pathophysiological processes in rheumatoid arthritis and atherosclerosis Rheumatology, January 1, 2009; 48(1): 11 - 22. [Abstract] [Full Text] [PDF]

				A. Schober Chemokines in Vascular Dysfunction and Remodeling Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 1950 - 1959. [Abstract] [Full Text] [PDF]

				T. M. Handel, Z. Johnson, D. H. Rodrigues, A. C. dos Santos, R. Cirillo, V. Muzio, S. Riva, M. Mack, M. Deruaz, F. Borlat, et al. An engineered monomer of CCL2 has anti-inflammatory properties emphasizing the importance of oligomerization for chemokine activity in vivo J. Leukoc. Biol., October 1, 2008; 84(4): 1101 - 1108. [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]

				E. A. Eugenin, S. Morgello, M. E. Klotman, A. Mosoian, P. A. Lento, J. W. Berman, and A. D. Schecter Human Immunodeficiency Virus (HIV) Infects Human Arterial Smooth Muscle Cells in Vivo and in Vitro: Implications for the Pathogenesis of HIV-Mediated Vascular Disease Am. J. Pathol., April 1, 2008; 172(4): 1100 - 1111. [Abstract] [Full Text] [PDF]

				K. Borensztajn, J. Stiekema, S. Nijmeijer, P. H. Reitsma, M. P. Peppelenbosch, and C. A. Spek Factor Xa Stimulates Proinflammatory and Profibrotic Responses in Fibroblasts via Protease-Activated Receptor-2 Activation Am. J. Pathol., February 1, 2008; 172(2): 309 - 320. [Abstract] [Full Text] [PDF]

				K. Egashira, K. Nakano, K. Ohtani, K. Funakoshi, G. Zhao, Y. Ihara, J.-i. Koga, S. Kimura, R. Tominaga, and K. Sunagawa Local Delivery of Anti-Monocyte Chemoattractant Protein-1 by Gene-Eluting Stents Attenuates In-Stent Stenosis in Rabbits and Monkeys Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2563 - 2568. [Abstract] [Full Text] [PDF]

				D. Burt, G. Salvidio, E. Tarabra, F. Barutta, S. Pinach, P. Dentelli, G. Camussi, P. C. Perin, and G. Gruden The Monocyte Chemoattractant Protein-1/Cognate CC Chemokine Receptor 2 System Affects Cell Motility in Cultured Human Podocytes Am. J. Pathol., December 1, 2007; 171(6): 1789 - 1799. [Abstract] [Full Text] [PDF]