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Antimonocyte chemoattractant protein-1 gene therapy reduces experimental in-stent restenosis in hypercholesterolemic rabbits and monkeys

Gene Therapy volume 11, pages 1273–1282 (2004)Cite this article

Abstract

In-stent restenosis results exclusively from neointimal hyperplasia due to mechanical injury and a foreign body response to the prosthesis. Inflammation mediated by monocyte chemoattractant protein-1 (MCP-1) might therefore underlie in-stent restenosis. We recently devised a new strategy for anti-MCP-1 gene therapy by transfecting an N-terminal deletion mutant of the MCP-1 gene into skeletal muscles. We used this strategy to investigate the role of MCP-1 in experimental in-stent restenosis in hypercholesterolemic rabbits and monkeys. Transfection of the mutant MCP-1 gene suppressed monocyte infiltration/activation in the stented arterial wall and markedly reduced the development of neointimal hyperplasia. This strategy also suppressed local expression of MCP-1 and inflammatory cytokines. Therefore, inhibition of MCP-1-mediated inflammation is effective in reducing experimental in-stent restenosis. This strategy might be a useful form of gene therapy against human in-stent restenosis.

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References

  1. Topol EJ, Serruys PW . Frontiers in interventional cardiology. Circulation 1998; 98: 1802–1820.

    Article  CAS  Google Scholar 

  2. Hoffmann R et al. Patterns and mechanisms of in-stent restenosis. A serial intravascular ultrasound study. Circulation 1996; 94: 1247–1254.

    Article  CAS  Google Scholar 

  3. Farb A et al. Pathology of acute and chronic coronary stenting in humans. Circulation 1999; 99: 44–52.

    Article  CAS  Google Scholar 

  4. Grewe PH et al. Acute and chronic tissue response to coronary stent implantation: pathologic findings in human specimen. J Am Coll Cardiol 2000; 35: 157–163.

    Article  CAS  Google Scholar 

  5. Kornowski R et al. In-stent restenosis: contributions of inflammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol 1998; 31: 224–230.

    Article  CAS  Google Scholar 

  6. Suzuki T et al. Stent-based delivery of sirolimus reduces neointimal formation in a porcine coronary model. Circulation 2001; 104: 1188–1193.

    Article  CAS  Google Scholar 

  7. Sousa JE et al. Sustained suppression of neointimal proliferation by sirolimus-eluting stents: one-year angiographic and intravascular ultrasound follow-up. Circulation 2001; 104: 2007–2011.

    Article  CAS  Google Scholar 

  8. Teirstein PS . Living the dream of no restenosis. Circulation 2001; 104: 1996–1998.

    Article  CAS  Google Scholar 

  9. Morice MC et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002; 346: 1773–1780.

    Article  CAS  Google Scholar 

  10. Farb A et al. Morphological predictors of restenosis after coronary stenting in humans. Circulation 2002; 105: 2974–2980.

    Article  Google Scholar 

  11. Sousa JE, Costa MA, Sousa AG . What is ‘the matter’ with restenosis in 2002? Circulation 2002; 105: 2932–2933.

    Article  Google Scholar 

  12. Welt FG, Rogers C . Inflammation and restenosis in the stent era. Arterioscler Thromb Vasc Biol 2002; 22: 1769–1776.

    Article  CAS  Google Scholar 

  13. Gerard C, Rollins BJ . Chemokines and disease. Nat Immunol 2001; 2: 108–115.

    Article  CAS  Google Scholar 

  14. Mukaida N, Harada A, Matsushima K . Interleukin-8 (IL-8) and monocyte chemotactic and activating factor (MCAF/MCP-1), chemokines essentially involved in inflammatory and immune reactions. Cytokine Growth Factor Rev 1998; 9: 9–23.

    Article  CAS  Google Scholar 

  15. Egashira K et al. Anti-monocyte chemoattractant protein-1 gene therapy inhibits vascular remodeling in rats: blockade of MCP-1 activity after intramuscular transfer of a mutant gene inhibits vascular remodeling induced by chronic blockade of NO synthesis. FASEB J 2000; 14: 1974–1978.

    Article  CAS  Google Scholar 

  16. Zhang Y, Rollins BJ . A dominant negative inhibitor indicates that monocyte chemoattractant protein 1 functions as a dimer. Mol Cell Biol 1995; 15: 4851–4855.

    Article  CAS  Google Scholar 

  17. Egashira K et al. Importance of monocyte chemoattractant protein-1 pathway in neointimal hyperplasia after periarterial injury in mice and monkeys. Circ Res 2002; 90: 1167–1172.

    Article  CAS  Google Scholar 

  18. Usui M et al. Anti-monocyte chemoattractant protein-1 gene therapy inhibits restenotic changes (neointimal hyperplasia) after balloon injury in rats and monkeys. FASEB J 2002; 16: 1838–1840.

    Article  CAS  Google Scholar 

  19. Mori E et al. Essential role of monocyte chemoattractant protein-1 in development of restenotic changes (neointimal hyperplasia and constrictive remodeling) after balloon angioplasty in hypercholesterolemic rabbits. Circulation 2002; 105: 2905–2910.

    Article  CAS  Google Scholar 

  20. Ni W et al. New anti-monocyte chemoattractant protein-1 gene therapy attenuates atherosclerosis in apolipoprotein E-knockout mice. Circulation 2001; 103: 2096–2101.

    Article  CAS  Google Scholar 

  21. Inoue S et al. Anti-monocyte chemoattractant protein-1 gene therapy limits progression and destabilization of established atherosclerosis in apolipoprotein E-knockout mice. Circulation 2002; 106: 2700–2706.

    Article  CAS  Google Scholar 

  22. Roque M et al. CCR2 deficiency decreases intimal hyperplasia after arterial injury. Arterioscler Thromb Vasc Biol 2002; 22: 554–559.

    Article  CAS  Google Scholar 

  23. Horvath C et al. Targeting CCR2 or CD18 inhibits experimental in-stent restenosis in primates: inhibitory potential depends on type of injury and leukocytes targeted. Circ Res 2002; 90: 488–494.

    Article  CAS  Google Scholar 

  24. Schwartz RS et al. Drug-eluting stents in preclinical studies: recommended evaluation from a consensus group. Circulation 2002; 106: 1867–1873.

    Article  Google Scholar 

  25. Rogers C, Edelman ER . Endovascular stent design dictates experimental restenosis and thrombosis. Circulation 1995; 91: 2995–3001.

    Article  CAS  Google Scholar 

  26. Rogers C, Edelman ER, Simon DI . A mAb to the beta2-leukocyte integrin Mac-1 (CD11b/CD18) reduces intimal thickening after angioplasty or stent implantation in rabbits. Proc Natl Acad Sci USA 1998; 95: 10134–10139.

    Article  CAS  Google Scholar 

  27. Cipollone F et al. Elevated circulating levels of monocyte chemoattractant protein-1 in patients with restenosis after coronary angioplasty. Arterioscler Thromb Vasc Biol 2001; 21: 327–334.

    Article  CAS  Google Scholar 

  28. Oshima S et al. Plasma monocyte chemoattractant protein-1 antigen levels and the risk of restenosis after coronary stent implantation. Jpn Circ J 2001; 65: 261–264.

    Article  CAS  Google Scholar 

  29. Farb A et al. Oral everolimus inhibits in-stent neointimal growth. Circulation 2002; 106: 2379–2384.

    Article  CAS  Google Scholar 

  30. Inadera H et al. Increase in circulating levels of monocyte chemoattractant protein-1 with aging. J Interferon Cytokine Res 1999; 19: 1179–1182.

    Article  CAS  Google Scholar 

  31. de Lemos JA et al. Association between plasma levels of monocyte chemoattractant protein-1 and long-term clinical outcomes in patients with acute coronary syndromes. Circulation 2003; 107: 690–695.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by Grants-in-Aid for Scientific Research (14657172, 14207036) from the Ministry of Education, Science, and Culture, Tokyo, Japan, by Health Science Research Grants (Comprehensive Research on Aging and Health, and Research on Translational Research) from the Ministry of Health Labor and Welfare, Tokyo, Japan, and by the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research, Tokyo, Japan.

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    K Ohtani, M Usui, K Nakano, S Kitamoto, A Takeshita & K Egashira

  2. Primate Research Center, Guandong, China

    Y Kohjimoto, S Kitajima & Y Hirouchi

  3. Gaoyao Kangda Laboratory Animals Science and Technology, Guandong, China

    X-H Li

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  1. K Ohtani
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Ohtani, K., Usui, M., Nakano, K. et al. Antimonocyte chemoattractant protein-1 gene therapy reduces experimental in-stent restenosis in hypercholesterolemic rabbits and monkeys. Gene Ther 11, 1273–1282 (2004). https://doi.org/10.1038/sj.gt.3302288

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  • DOI: https://doi.org/10.1038/sj.gt.3302288

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