title: 3-[(dodecylthiocarbonyl)methyl]-glutarimide attenuates graft arterial disease by suppressing alloimmune responses and vascular smooth muscle cell proliferation.
abstract: BACKGROUND
  Graft arterial disease (GAD) is a major cause of late graft loss after organ transplantation. Alloimmune responses and vascular remodeling eventually cause the transplant organ to develop GAD. In this study, we aimed to limit the development of GAD by inhibiting alloimmune responses and vascular smooth muscle cell (VSMC) proliferation with a new compound, 3-[(dodecylthiocarbonyl)methyl]-glutarimide ([DTCM]-glutarimide), in a murine cardiac model of GAD.
  
  
  METHODS
  The hearts from B6.CH-2 mice were transplanted into C57BL/6 mouse recipients to examine the extent of GAD. The recipients were treated with either vehicle or DTCM-glutarimide intraperitoneally (40 mg/kg per day) for 4 weeks.
  
  
  RESULTS
  The administration of DTCM-glutarimide attenuated GAD formation (luminal occlusion: 37.9 ± 5.9% vs 14.8 ± 5.4%, P < 0.05) by inhibiting the number of graft-infiltrating cells and decreasing alloreactive interferon (IFN)-γ production compared with control mice, as measured by the Enzyme-linked ImmunoSpot assay. In vitro, VSMCs proliferated on stimulation with either basic fibroblast growth factor or IFN-γ and splenocytes after transplantation, but the addition of DTCM-glutarimide resulted in the inhibition of VSMC proliferation. Moreover, DTCM-glutarimide suppressed cyclin D1 expression and inhibited cell cycle progression from G1 to S in VSMCs.
  
  
  CONCLUSIONS
  The compound DTCM-glutarimide suppressed GAD development by inhibiting not only alloimmune responses but also VSMC proliferation in the graft.
authors: 1 Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan. 2 Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan. 3 Department of Molecular Target Medicine Screening, Aichi Medical University School of Medicine, Nagakude, Japan.
authors: Masaaki
authors: M
authors: Zaitsu
authors: Kenichiro
authors: K
authors: Yamashita
authors: Susumu
authors: S
authors: Shibasaki
authors: Yusuke
authors: Y
authors: Tsunetoshi
authors: Moto
authors: M
authors: Fukai
authors: Masaomi
authors: M
authors: Ogura
authors: Tadashi
authors: T
authors: Yoshida
authors: Rumi
authors: R
authors: Igarashi
authors: Nozomi
authors: N
authors: Kobayashi
authors: Kazuo
authors: K
authors: Umezawa
authors: Satoru
authors: S
authors: Todo
mesh_terms: D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy*; D002478:Cells, Cultured; D016027:Heart Transplantation / Q000009:adverse effects*; D006650:Histocompatibility Testing; D007371:Interferon-gamma / Q000494:pharmacology; D007518:Isoantibodies / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000473:pathology*; D010881:Piperidones / Q000494:pharmacology*; D014184:Transplantation, Homologous
chemical_list: C573776:3-((dodecylthiocarbonyl)methyl)glutarimide; D007518:Isoantibodies; D010881:Piperidones; D007371:Interferon-gamma