Combination of clopidogrel and everolimus dramatically reduced the development of transplant arteriosclerosis in murine aortic allografts

Summary Our group has shown that platelet inhibition with clopidogrel, an antagonist of the P2Y12 adenosine diphosphate receptor on platelets, reduced the formation of transplant arteriosclerosis. The aim of this study was to investigate whether a combination of cyclosporin or everolimus with clopid...

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Bibliographic Details
Published in:Transplant international 2010-09, Vol.23 (9), p.959-966
Main Authors: Eckl, Sebastian, Heim, Christian, Abele‐Ohl, Silke, Hoffmann, Julia, Ramsperger‐Gleixner, Martina, Weyand, Michael, Ensminger, Stephan M.
Format: Article
Language:English
Subjects:
Animals
Aorta, Abdominal - transplantation
Arteriosclerosis - complications
Arteriosclerosis - metabolism
Arteriosclerosis - prevention & control
clopidogrel
Disease Models, Animal
Drug Therapy, Combination
Everolimus
Graft Rejection - etiology
Graft Rejection - metabolism
Graft Rejection - prevention & control
Immunosuppressive Agents - pharmacokinetics
Immunosuppressive Agents - therapeutic use
mammalian target of rapamycin inhibitor
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Platelet Aggregation - drug effects
Platelet Aggregation Inhibitors - pharmacokinetics
Platelet Aggregation Inhibitors - therapeutic use
platelets
Sirolimus - analogs & derivatives
Sirolimus - pharmacokinetics
Sirolimus - therapeutic use
Ticlopidine - analogs & derivatives
Ticlopidine - pharmacokinetics
Ticlopidine - therapeutic use
transplant arteriosclerosis
Transplantation, Homologous
Treatment Outcome
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Summary:Summary Our group has shown that platelet inhibition with clopidogrel, an antagonist of the P2Y12 adenosine diphosphate receptor on platelets, reduced the formation of transplant arteriosclerosis. The aim of this study was to investigate whether a combination of cyclosporin or everolimus with clopidogrel has a beneficial effect on the development of transplant arteriosclerosis. Fully MHC mismatched C57Bl/6 (H2b) donor aortas were transplanted into CBA.J (H2k) recipients and mice received either clopidogrel alone (1 mg/kg/day) or in combination with cyclosporin (2 mg/kg/day) or everolimus (0.05 mg/kg/day). Grafts were analysed by histology and morphometry on day 30 after transplantation. In mice treated with clopidogrel alone, transplant arteriosclerosis was significantly reduced [intima proliferation 56 ± 11% vs. 81 ± 7% (control)/n = 7]. Daily application of everolimus reduced the development of transplant arteriosclerosis compared with untreated controls [intima proliferation of 29 ± 9% vs. 81 ± 7% (control)/n = 7]. Strikingly, combination of clopidogrel and everolimus almost abolished the formation of transplant arteriosclerosis [intima proliferation: 11 ± 8% vs. 81 ± 7% (control)/n = 7]. By contrast, combination of cyclosporin and clopidogrel compared with clopidogrel alone showed no additive effect. These results demonstrate that combination of platelet‐ and mammalian target of Rapamycin‐inhibition can dramatically reduce the development of transplant arteriosclerosis.
ISSN:0934-0874
1432-2277
DOI:10.1111/j.1432-2277.2010.01072.x