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.

Keywords:
Chemokines, Intimal hyperplasia, MCP-1, Smooth muscle cell, Transplantation
1.
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.
2.
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.
3.
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.
4.
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.
5.
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.
6.
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.
7.
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.
8.
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.
9.
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.
10.
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.
11.
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.
12.
Luster AD: Chemokines – chemotactic cytokines that mediate inflammation. N Engl J Med 1998;338:436–445.
13.
Gu L, Tseng SC, Rollins BJ: Monocyte chemoattractant protein-1. Chem Immunol 1999;72:7–29.
14.
Charo IF: CCR2: from cloning to the creation of knockout mice. Chem Immunol 1999;72:30–41.
15.
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.
16.
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.
17.
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.
18.
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.
19.
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.
20.
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.
21.
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.
22.
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.
23.
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.
24.
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.
25.
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.
26.
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.
27.
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.
28.
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.
29.
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.
30.
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.
31.
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.
32.
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.
33.
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.
34.
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.
35.
Hancock WW: Chemokines and transplant immunobiology. J Am Soc Nephrol 2002;13:821–824.
36.
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.
37.
Libby P, Pober JS: Chronic rejection. Immunity 2001;14:387–397.
38.
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.
39.
Schmid C, Heemann U, Azuma H, Tilney NL: Rapamycin inhibits transplant vasculopathy in long-surviving rat heart allografts. Transplantation 1995;60:729–733.
40.
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.
41.
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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2008
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