Abstract 1674: Telmisartan Attenuates Chronic Allograft Rejection via PPARγ Activity
Background: Chronic rejection remains the most common cause of graft failure after transplantation, although cardiac transplantation is an established therapy for patients with end-stage heart disease. Recently, it has been reported that telmisartan can function as a partial agonist of peroxisome proliferator-activated receptor-γ (PPARγ). We have reported that PPARγ agonist plays an important role in regulating allograft rejection. To investigate the effect of telmisartan treatment in chronic rejection, we performed murine cardiac transplantation.
Methods and Results: To investigate the effect of telmisartan for chronic rejection, hearts from Bm12 mice were transplanted into C57BL/6 (B/6) mice (class II mismatch) and allografts were harvested at 8 weeks after cardiac transplantation. Recipient mice were orally given either control chow or chow containing telmisartan (10 mg/kg/day) from 1 day before cardiac transplantation. Although severe neointimal hyperplasia developed in cardiac allografts from mice receiving control chow (luminal occlusion: 67.3 ± 8.5 %), neointimal hyperplasia was significantly attenuated in cardiac allografts from mice treated with telmisartan (29.4 ± 7.9 %, p<0.001). RNase protection assays (RPA) showed that expression of IFN-γ in cardiac allogarfts was significantly suppressed in telmisartan-treatment group compared with the control group. We performed mixed lymphocyte reaction (MLR) and proliferation assays of smooth muscle cells (SMCs) in vitro. T cell proliferation was inhibited by the addition of telmisartan to MLR. SMC proliferation by fetal bovine serum (FBS) was significantly suppressed because of the addition of telmisartan (1 μM). The PPARγ antagonist (GW9662) significantly blocked suppression of SMC proliferation by telmisartan.
Conclusions: Telmisartan attenuated SMC proliferation via PPARγ activity and suppressed neointimal hyperplasia after transplantation. Telmisartan has promise in suppressing chronic allograft rejection.