title: Inhibition of intimal hyperplasia in murine aortic allografts by the oral administration of the transforming growth factor-beta receptor I kinase inhibitor SD-208.
abstract: 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.
  
  
  CONCLUSIONS
  These results demonstrate that SD-208 can effectively reduce the formation of intimal hyperplasia of TA in the murine aortic allograft model.
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Departments of Cardiovascular Medicine.
authors.forename: Ping
authors.initials: P
authors.lastname: Ye
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan.
authors.forename: Anchen
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan.
authors.forename: Linyun
authors.initials: L
authors.lastname: Ren
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan.
authors.forename: Chao
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan.
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan.
authors.forename: Peng
authors.initials: P
authors.lastname: Deng
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan.
authors.forename: Chuangyan
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Yue
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan; Cardiovascular Surgery, Central Hospital of Wuhan, Wuhan, China. Electronic address: jiahong.xia@mail.hust.edu.cn.
authors.forename: Jiahong
authors.initials: J
authors.lastname: Xia
mesh_terms: D000284:Administration, Oral; D064591:Allografts / Q000473:pathology*; D000818:Animals; D001011:Aorta / Q000473:pathology* / Q000637:transplantation*; D001161:Arteriosclerosis / Q000473:pathology / Q000517:prevention & control*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006965:Hyperplasia / Q000473:pathology / Q000517:prevention & control; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D058426:Neointima / Q000473:pathology; D011621:Pteridines / Q000008:administration & dosage*; D017539:Tunica Intima / Q000473:pathology*
chemical_list: D011621:Pteridines; C511004:SD-208
keywords: Smad3; TGF-β; TGF-β receptor I kinase inhibitor; connective tissue growth factor; intimal hyperplasia; smooth muscle-like cell; transplant arteriosclerosis