EFFECTS OF PRAVASTATIN ON CHRONIC REJECTION OF RAT CARDIAC ALLOGRAFTS

Background. Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reduc tase inhibitor, inhibits coronary transplant vasculopathy in the clini cal setting, To further delineate the immune modulatory effect of this agent, it was tested in a rat cardiac transplant model of chronic rej ection. Methods, Rat heterotopic abdominal cardiac transplants were pe rformed using a Lewis to Fischer 344 combination. Fischer 344 recipien ts received a brief course of cyclosporine to decrease the incidence o f acute rejection, Experimental groups were treated with either high-d ose (10 mg/kg) or low-dose (5 mg/kg) pravastatin for 120 days, while a control group did not receive pravastatin. The effect of pravastatin on chronic rejection of cardiac allografts was analyzed by histology, and the expression of laminin, fibronectin, macrophages, and T cells w as assessed by immunohistochemistry. Results, Coronary transplant vasc ulopathy was inhibited in both groups of pravastatin-treated animals, as compared with controls, Immunohistochemistry revealed that control animals had degraded laminin and fibronectin which paralleled the degr ee of tissue necrosis. In contrast, pravastatin-treated animals had mo dest amounts of extracellular matrix proteins retained within intermyo cytes and endothelium, a pattern seen in native cardiac tissue, The pr avastatin-treated groups also had fewer graft-infiltrating macrophages , specifically within the arterial intima and perivascular areas, Conc lusions, progressive chronic vascular rejection, a leading cause of al lograft failure, can be inhibited by pravastatin in a well-defined rat cardiac transplant model. Pravastatin appears to inhibit the synthesi s and subsequent degradation of extracellular matrix proteins and bloc k the infiltration of macrophages to the graft, which emphasizes that this inflammatory cell plays a major role in the pathogenesis of trans plant chronic rejection.