Inhibition of intimal hyperplasia in murine aortic allografts by the oral administration of the transforming growth factor-beta receptor I kinase inhibitor SD-208.

BACKGROUND

Transforming growth factor-beta (TGF-β) plays a significant role in the pathogenesis of the intimal hyperplasia of transplant arteriosclerosis (TA). The aim of this study was to evaluate the efficacy of an oral inhibitor of TGF-β receptor I kinase (SD-208) on the development of TA.

METHODS

BALB/c (H-2(d)) donor aortas were transplanted into C57BL/6 (H-2(b)) recipients, and the mice then received different doses (40 or 60 mg/kg) of SD-208 or control vehicle by daily gavage for 8 weeks. The grafts were analyzed by histology and morphometry at 1, 2, 4, 6 and 8 weeks after transplantation. The effects of TGF-β and SD-208 on neointimal smooth muscle-like cell (SMLC) and vascular smooth muscle cell (VSMC) proliferation and migration were evaluated, and the expression levels of Smad3, P-Smad3, connective tissue growth factor (CTGF) and collagen I were determined by in vitro experiments.

RESULTS

The intimal hyperplasia of the SD-208-treated group was significantly reduced compared with the vehicle-treated control group (32% and 48% reduction for 40 mg/kg and 60 mg/kg SD-208 compared with the controls, respectively [n = 5], p < 0.05). SD-208 reduced SMLC proliferation and the production of intimal collagen by 21% and 75%, respectively, in the grafts. SD-208 also abolished the promoting effect of TGF-β on SMLC proliferation and migration but did not affect TGF-β inhibition of VSMCs in vitro. CTGF, a protein downstream of TGF-β, was downregulated with the inhibition of Smad3 phosphorylation by SD-208, both in vitro and in vivo. Moreover, we found that the endogenous Smad3 in SMLCs was upregulated from 2 weeks after transplantation and was 64% higher than in VSMCs at 8 weeks.

CONCLUSION

These results demonstrate that SD-208 can effectively reduce the formation of intimal hyperplasia of TA in the murine aortic allograft model.