Perivascular Treatment with Azathioprine Reduces Neointimal Hyperplasia in Experimental Vein Grafts
DOI:
https://doi.org/10.1532/HSF98.20051168Abstract
Background. Azathioprine is an immunosuppressive and anti-inflammatory drug, and it has been shown to induce apoptosis in human T-lymphocytes. We investigated whether local treatment with azathioprine can inhibit neointimal hyperplasia in experimental vein grafts.
Methods. C57BL/6J mice underwent interposition of the inferior vena cava from isogenic donor mice into the common carotid artery using a cuff technique. In the treatment group azathioprine was perivascularly applied. The control group did not receive local treatment. Vein grafts were harvested at 1 and 2 weeks postoperatively and underwent morphometric analysis as well as immunohistochemical analysis for apoptosis (TUNEL).
Results. In grafted veins without treatment (controls), neointimal thickness was 10 m m (range, 6-29 m m), and 12 m m (range, 8-40 m) at 1 and 2 weeks postoperatively, respectively. In azathioprine-treated grafts, the neointimal thickness was 2 m m (range, 1-5 m m) and 4 m m (range, 3-11 m m) at 1 and 2 weeks postoperatively, respectively. This reduction of neointimal thickness was significant at 1 week (P = .001) and 2 weeks (P = .016) postoperatively.
Azathioprine-treated vein grafts showed an increased rate of apoptosis in the vascular wall as compared with controls (593 [range, 26-783] versus 45 [range, 0-106] apoptotic cells/mm2 at 1 week, P = .063; and 656 [range, 327-1270] versus 19 [range, 0-79] apoptotic cells/mm2 at 2 weeks, P = .016).
Conclusion. We conclude that treatment of experimental vein grafts with azathioprine is associated with a reduction of neointimal hyperplasia and an increased apoptosis rate in the vascular wall. These results suggest that azathioprine may be useful for the prevention of vein graft disease after coronary artery bypass grafting.
References
Belgi G, Friedmann PS. 2002. Traditional therapies: glucocorticoids, azathioprine, methotrexate, hydroxyurea. Z Hautkr 77:624-32.nMaltzman JS, Koretzky GA. 2003. Azathioprine: old drug, new actions. J Clin Invest 111:1122-24.nMingoli A, Edwards JD, Feldhaus RJ, et al. 1996. Fresh vein allograft survival in dogs after cyclosporine treatment. J Surg Res 62:95-102.nSchachner T, Zou Y, Oberhuber A, et al. 2004. Local application of rapamycin inhibits neointimal hyperplasia in experimental vein grafts.nAnn Thorac Surg 77:1580-85.nZou Y, Dietrich H, Hu Y, Metzler B, Wick G, Xu Q. 1998. Mouse model of venous bypass graft disease. Am J Pathol 153:1301-10.nSchachner T, Oberhuber A, Zou Y, et al. 2005. Rapamycin treatment is associated with an increased apoptosis rate in experimental vein grafts. Eur J Cardio Thorac Surg 27:302-6.nSchachner T, Zou Y, Oberhuber A, et al. 2004. Perivascular application of C-type natriuretic peptide attenuates neointimal hyperplasia in experimental vein grafts. Eur J Cardiothorac Surg 25:585-90.nSchwab M, Herrlinger K, Schaeffeler E, Stange EF. 2003. Therapiechronisch entzündlicher darmerkrankungen mit azathioprin, 6-Mercaptopurin und 6-Thioguanin [in German]. Dtsch Med Wochenschr 128:378-85.nTiede I, Fritz G, Strand S, et al. 2003. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest 111:1133-45.nArruda JA, Costa MA, Brito FS, et al. 2003. Effect of systemic immuno suppression on coronary in-stent intimal hyperplasia in renal transplant patients. Am J Cardiol 91:1363-5.n
