Inhibition of MCP-1/CCR2 Signaling Does Not Inhibit Intimal Proliferation in a Mouse Aortic Transplant ModelAlexis J.D.a · Pyo R.T.b, c · Chereshnev I.b, c · Katz J.f · Rollins B.J.d · Charo I.F.e · Taubman M.B.a
aAab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, N.Y., bZena and Michael A. Wiener Cardiovascular Institute and cDepartment of Medicine, Mount Sinai School of Medicine, New York, N.Y., dDepartment of Adult Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass., and eGladstone Institute of Cardiovascular Disease, University of California, San Francisco, San Francisco, Calif., USA; fSackler School of Medicine, Tel Aviv, Israel
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Background: Transplant arteriopathy is the leading cause of long term morbidity and mortality following heart transplantation. Animal models have demonstrated that monocyte chemoattractant protein (MCP)-1 is induced early after transplant in cardiac and aortic allografts. We have previously reported that deficiency of MCP-1 or its receptor, CC chemokine receptor 2 (CCR2), is associated with a reduction in intimal proliferation in a mouse femoral artery injury model. Using knockout mice, we have now examined the role of MCP-1 and CCR2 in the development of the intimal proliferation of transplant arteriopathy. Methods: C57Bl/6 CCR2 and MCP-1 wild-type and knockout mice were used in the studies and aortic transplants were performed between Balb/c mice and C57Bl/6 mice. Aortas from recipient animals were harvested 8 weeks after transplant. Results: Unlike arterial injury, in an aortic transplant model inhibition of MCP-1/CCR2 signaling did not result in reduced intimal proliferation. Conclusions: Despite a pathology that appears similar, the inflammatory mediators that regulate transplant arteriopathy differ from those regulating intimal proliferation secondary to wire injury. Our results suggest that targeting MCP-1/CCR2 signaling is not sufficient to block transplant arteriopathy across a complete MHC-mismatch barrier.
© 2008 S. Karger AG, Basel
- Sarris GE, Moore KA, Schroeder JS, Hunt SA, Fowler MB, Valantine HB, Vagelos RH, Billingham ME, Oyer PE, Stinson EB, et al: Cardiac transplantation: the Stanford experience in the cyclosporine era. J Thorac Cardiovasc Surg 1994;108:240–251; discussion 251–252.
- Schroeder JS, Gao SZ, Alderman EL, Hunt SA, Johnstone I, Boothroyd DB, Wiederhold V, Stinson EB: A preliminary study of diltiazem in the prevention of coronary artery disease in heart-transplant recipients. N Engl J Med 1993;328:164–170.
- Gao SZ, Schroeder JS, Alderman EL, Hunt SA, Silverman JF, Wiederhold V, Stinson EB: Clinical and laboratory correlates of accelerated coronary artery disease in the cardiac transplant patient. Circulation 1987;76:V56–V61.
Gao SZ, Schroeder JS, Alderman EL, Hunt SA, Valantine HA, Wiederhold V, Stinson EB: Prevalence of accelerated coronary artery disease in heart transplant survivors. Comparison of cyclosporine and azathioprine regimens. Circulation 1989;80:III100–III105.
- Uretsky BF, Murali S, Reddy PS, Rabin B, Lee A, Griffith BP, Hardesty RL, Trento A, Bahnson HT: Development of coronary artery disease in cardiac transplant patients receiving immunosuppressive therapy with cyclosporine and prednisone. Circulation 1987;76:827–834.
- Taylor DO, Edwards LB, Boucek MM, Trulock EP, Deng MC, Keck BM, Hertz MI: Registry of the International Society for Heart and Lung Transplantation: twenty-second official adult heart transplant report – 2005. J Heart Lung Transplant 2005;24:945–955.
- Shi C, Lee WS, He Q, Zhang D, Fletcher DL, Jr., Newell JB, Haber E: Immunologic basis of transplant-associated arteriosclerosis. Proc Natl Acad Sci USA 1996;93:4051–4056.
- Mennander A, Tiisala S, Halttunen J, Yilmaz S, Paavonen T, Hayry P: Chronic rejection in rat aortic allografts. An experimental model for transplant arteriosclerosis. Arterioscler Thromb 1991;11:671–680.
- Koulack J, McAlister VC, Giacomantonio CA, Bitter-Suermann H, MacDonald AS, Lee TD: Development of a mouse aortic transplant model of chronic rejection. Microsurgery 1995;16:110–113.
- Corry RJ, Winn HJ, Russell PS: Primarily vascularized allografts of hearts in mice. The role of H-2D, H-2K, and non-H-2 antigens in rejection. Transplantation 1973;16:343–350.
- Cramer DV, Wu GD, Chapman FA, Cajulis E, Wang HK, Makowka L: Lymphocytic subsets and histopathologic changes associated with the development of heart transplant arteriosclerosis. J Heart Lung Transplant 1992;11:458–466.
- Luster AD: Chemokines – chemotactic cytokines that mediate inflammation. N Engl J Med 1998;338:436–445.
- Gu L, Tseng SC, Rollins BJ: Monocyte chemoattractant protein-1. Chem Immunol 1999;72:7–29.
- Charo IF: CCR2: from cloning to the creation of knockout mice. Chem Immunol 1999;72:30–41.
- Russell ME, Adams DH, Wyner LR, Yamashita Y, Halnon NJ, Karnovsky MJ: Early and persistent induction of monocyte chemoattractant protein 1 in rat cardiac allografts. Proc Natl Acad Sci USA 1993;90:6086–6090.
- Horiguchi K, Kitagawa-Sakakida S, Sawa Y, Li ZZ, Fukushima N, Shirakura R, Matsuda H: Selective chemokine and receptor gene expressions in allografts that develop transplant vasculopathy. J Heart Lung Transplant 2002;21:1090–1100.
- Furukawa Y, Matsumori A, Ohashi N, Shioi T, Ono K, Harada A, Matsushima K, Sasayama S: Anti-monocyte chemoattractant protein-1/monocyte chemotactic and activating factor antibody inhibits neointimal hyperplasia in injured rat carotid arteries. Circ Res 1999;84:306–314.
- Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA, Starling RC, Sørensen K, Hummel M, Lind JM, Abeywickrama KH, Bernhardt P: Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 2003;349:847–858.
- Roque M, Kim WJ, Gazdoin M, Malik A, Reis ED, Fallon JT, Badimon JJ, Charo IF, Taubman MB: CCR2 deficiency decreases intimal hyperplasia after arterial injury. Arterioscler Thromb Vasc Biol 2002;22:554–559.
- Kim WJ, Chereshnev I, Gazdoiu M, Fallon JT, Rollins BJ, Taubman MB: MCP-1 deficiency is associated with reduced intimal hyperplasia after arterial injury. Biochem Biophys Res Commun 2003;310:936–942.
- Autieri MV, Carbone C, Mu A: Expression of allograft inflammatory factor-1 is a marker of activated human vascular smooth muscle cells and arterial injury. Arterioscler Thromb Vasc Biol 2000;20:1737–1744.
- Lu B, Rutledge BJ, Gu L, Fiorillo J, Lukacs NW, Kunkel SL, North R, Gerard C, Rollins BJ: Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J Exp Med 1998;187:601–608.
- Boring L, Gosling J, Cleary M, Charo IF: Decreased lesion formation in CCR2–/– mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 1998;394:894–897.
- Roque M, Fallon JT, Badimon JJ, Zhang WX, Taubman MB, Reis ED: Mouse model of femoral artery denudation injury associated with the rapid accumulation of adhesion molecules on the luminal surface and recruitment of neutrophils. Arterioscler Thromb Vasc Biol 2000;20:335–342.
- Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, Libby P, Rollins BJ: Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell 1998;2:275–281.
- Dawson TC, Kuziel WA, Osahar TA, Maeda N: Absence of CC chemokine receptor-2 reduces atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis 1999;143:205–211.
- Belperio JA, Keane MP, Burdick MD, Lynch JP 3rd, Xue YY, Berlin A, Ross DJ, Kunkel SL, Charo IF, Strieter RM: Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome. J Clin Invest 2001;108:547–556.
- Yun JJ, Fischbein MP, Whiting D, Irie Y, Fishbein MC, Burdick MD, Belperio J, Strieter RM, Laks H, Berliner JA, Ardehali A: The role of MIG/CXCL9 in cardiac allograft vasculopathy. Am J Pathol 2002;161:1307–1313.
- Yun JJ, Fischbein MP, Laks H, Fishbein MC, Espejo ML, Ebrahimi K, Irie Y, Berliner J, Ardehali A: Early and late chemokine production correlates with cellular recruitment in cardiac allograft vasculopathy. Transplantation 2000;69:2515–2524.
- Akashi S, Sho M, Kashizuka H, Hamada K, Ikeda N, Kuzumoto Y, Tsurui Y, Nomi T, Mizuno T, Kanehiro H, Hisanaga M, Ko S, Nakajima Y: A novel small-molecule compound targeting CCR5 and CXCR3 prevents acute and chronic allograft rejection. Transplantation 2005;80:378–384.
- Yun JJ, Whiting D, Fischbein MP, Banerji A, Irie Y, Stein D, Fishbein MC, Proudfoot AE, Laks H, Berliner JA, Ardehali A: Combined blockade of the chemokine receptors CCR1 and CCR5 attenuates chronic rejection. Circulation 2004;109:932–937.
- Gao W, Faia KL, Csizmadia V, Smiley ST, Soler D, King JA, Danoff TM, Hancock WW: Beneficial effects of targeting CCR5 in allograft recipients. Transplantation 2001;72:1199–1205.
- Gao W, Topham PS, King JA, Smiley ST, Csizmadia V, Lu B, Gerard CJ, Hancock WW: Targeting of the chemokine receptor CCR1 suppresses development of acute and chronic cardiac allograft rejection. J Clin Invest 2000;105:35–44.
- Liu L, Dai E, Miller L, Seet B, Lalani A, Macauley C, Li X, Virgin HW, Bunce C, Turner P, Moyer R, McFadden G, Lucas A: Viral chemokine-binding proteins inhibit inflammatory responses and aortic allograft transplant vasculopathy in rat models. Transplantation 2004;77:1652–1660.
- Hancock WW: Chemokines and transplant immunobiology. J Am Soc Nephrol 2002;13:821–824.
- Saiura A, Sata M, Hiasa K, Kitamoto S, Washida M, Egashira K, Nagai R, Makuuchi M: Antimonocyte chemoattractant protein-1 gene therapy attenuates graft vasculopathy. Arterioscler Thromb Vasc Biol 2004;24:1886–1890.
- Libby P, Pober JS: Chronic rejection. Immunity 2001;14:387–397.
- Bigaud M, Schraa EO, Andriambeloson E, Lobstein V, Pally C, Kobel T, Bruns C, Zerwes HG: Complete loss of functional smooth muscle cells precedes vascular remodeling in rat aorta allografts. Transplantation 1999;68:1701–1707.
- Schmid C, Heemann U, Azuma H, Tilney NL: Rapamycin inhibits transplant vasculopathy in long-surviving rat heart allografts. Transplantation 1995;60:729–733.
- Murphy GJ, Bicknell GR, Nicholson ML: Rapamycin inhibits vascular remodeling in an experimental model of allograft vasculopathy and attenuates associated changes in fibrosis-associated gene expression. J Heart Lung Transplant 2003;22:533–541.
- Cole OJ, Shehata M, Rigg KM: Effect of SDZ RAD on transplant arteriosclerosis in the rat aortic model. Transplant Proc 1998;30:2200–2203.
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