The angiotensin I type 1 receptor blocker candesartan attenuates graft vasculopathy

Objective. Transplant arteriosclerosis remains the major cause of graft failure after cardiac transplantation, although recent progress in immunosuppressive therapy has dramatically improved short-term survival of recipient. We investigated the effects of the angiotensin II type 1 receptor (AT,R) blocker candesartan on the development of transplant arteriosclerosis in a murine model of cardiac transplantation. Materials and Methods. Hearts from DBA/2 (H-2(d)) mice were heterotopically transplanted into B10.D2 (H-2(d)) mice. Recipients were treated with oral administration of candesartan (1 mg/kg per day) or vehicle. Allografts were analyzed at 14 or 30 days after transplantation. Results. Candesartan significantly reduced the development of coronary arteriosclerosis (intima/media ratio: 0.86 +/- 0.09 versus 0.57 +/- 0.10, P < 0.05), without affecting the degree of parenchymal rejection at 30 days. There was no significant difference in the expression of adhesion molecules and cytokines at 14 days. Candesartan significantly reduced the number of peripheral mononuclear cells that differentiated into smooth muscle-like cells in the presence of basic fibroblast growth factor and platelet-derived growth factor BB (27.1 +/- 3.1 versus 17.3 +/- 1.8 cells/HPF, P < 0.05). Conclusions. Angiotensin II may play a role in the pathogenesis of transplant arteriosclerosis. Blockade of AT,R might be effective as a prophylactic therapy for transplant arteriosclerosis along with conventional immunosuppressive drugs. (c) 2005 Elsevier Inc. All rights reserved.