The angiotensin II 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(1)R) blocker candesartan on the development of transplant arteriosclerosis in a murine model of cardiac transplantation.


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(1)R might be effective as a prophylactic therapy for transplant arteriosclerosis along with conventional immunosuppressive drugs.
Yamamoto
Tetsufumi
T
Department of Cardiothoracic Surgery, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Sata
Masataka
M
Fukuda
Daiju
D
Takamoto
Shinichi
S
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001161:Arteriosclerosis / Q000473:pathology / Q000517:prevention & control*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D016027:Heart Transplantation / Q000473:pathology / Q000502:physiology*; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D011183:Postoperative Complications / Q000517:prevention & control*; D013777:Tetrazoles / Q000494:pharmacology*; D018183:Transplantation Chimera; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D014652:Vascular Diseases / Q000517:prevention & control*
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D015850:Interleukin-6; D013777:Tetrazoles; C081643:candesartan