TY - JOUR
T1 - 3-[(Dodecylthiocarbonyl)Methyl]-glutarimide attenuates graft arterial disease by suppressing alloimmune responses and vascular smooth muscle cell proliferation
AU - Zaitsu, Masaaki
AU - Yamashita, Kenichiro
AU - Shibasaki, Susumu
AU - Tsunetoshi, Yusuke
AU - Fukai, Moto
AU - Ogura, Masaomi
AU - Yoshida, Tadashi
AU - Igarashi, Rumi
AU - Kobayashi, Nozomi
AU - Umezawa, Kazuo
AU - Todo, Satoru
N1 - Publisher Copyright:
© Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2015/5/3
Y1 - 2015/5/3
N2 - 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 bm12 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.
AB - 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 bm12 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.
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U2 - 10.1097/TP.0000000000000576
DO - 10.1097/TP.0000000000000576
M3 - Article
C2 - 25675200
AN - SCOPUS:84930361882
SN - 0041-1337
VL - 99
SP - 948
EP - 956
JO - Transplantation
JF - Transplantation
IS - 5
ER -