The angiotensin II type 1 receptor blockervalsartan attenuates graft vasculopathy

Objective Transplant arteriosclerosis remains the major cause ofgraft failure after cardiac transplantation. Here, we investigated the effects ofthe angiotensin II type 1 receptor blocker valsartan on the development oftransplant arteriosclerosis in a murine model of cardiac transplantation. Methods Hearts from DBA/2 (H–2^d) mice were heterotopically transplantedinto B10.D2 (H–2^d) mice. Recipients were treated with oral administration ofvalsartan (10 mg/kg/day) or vehicle. Results Morphometrical analysis of thecardiac allografts harvested at 30 days revealed that valsartan significantlyreduced the development of coronary atherosclerosis (intima/media ratio:0.39 ± 0.05 vs. 0.66 ± 0.08, P < 0.01). At two weeks after transplantation, therewas no significant difference between the two groups in expression of adhesionmolecules and cytokines. Valsartan significantly reduced the number ofperipheral mononuclear cells that differentiated into smooth muscle–likecells in the presence of basic fibroblast growth factor and platelet–derivedgrowth factor BB (18.0 ± 1.5 vs. 30.3 ± 4.4 cells/HPF, P = 0.01). Conclusions These results suggest that angiotensin II plays a role in the pathogenesis oftransplant arteriosclerosis and that blockade of angiotensin II type 1 receptormight be effective as a prophylactic therapy for transplant arteriosclerosisalong with conventional immunosuppressive drugs.