Involvement of Platelet Activation by P2Y12 Receptor in the Development of Transplant Arteriosclerosis in Mice
Involvement of Platelet Activation by P2Y12 Receptor in the Development of Transplant Arteriosclerosis in Mice
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DOI：
10.1097/tp.0b013e318196305a
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发表时间：
2009-03
期刊：
影响因子：
6.2
通讯作者：
K. Yashiro;Y. Matsumoto;H. Ihara;Yasuhiro Suzuki;K. Kondo;T. Urano;K. Umemura
中科院分区：
文献类型：
--
作者：
K. Yashiro;Y. Matsumoto;H. Ihara;Yasuhiro Suzuki;K. Kondo;T. Urano;K. Umemura
背景虽然活化的血小板通过血小板内介质影响移植中的炎症，但其参与移植动脉硬化进展的机制尚未阐明。因此，我们研究了这个问题，使用P2 Y12受体敲除（KO）小鼠，其中血小板不能聚集腺苷二磷酸刺激。方法.将来自129 X1小鼠的颈动脉原位移植到野生型或KO小鼠中的次要抗原-错配品系组合中。未使用免疫抑制剂。移植后7、14、28和56天收集移植物进行形态计量学和免疫组织学检查。移植后7天和14天进行荧光激活细胞分选和定量实时逆转录酶聚合酶链反应。结果与野生型小鼠相比，KO小鼠移植物的内膜/中膜比率在移植后14、28和56天显著降低。免疫活化细胞分选分析显示，移植后14天，KO小鼠血小板CD 154表达和血小板-白细胞聚集体显著减少。此外，细胞间粘附分子-1和CD 40 mRNA的水平，以及细胞间粘附分子-1-或CD 40-阳性细胞在移植物中的数量在KO小鼠在移植后7天和14天较低。这些减少导致移植后14天KO小鼠中粘附于移植物血管壁的CD 45阳性白细胞显著减少。结论P2 Y12受体缺陷导致的血小板功能下降通过减少移植后早期移植物中粘附分子的表达和白细胞的积累，减弱了小鼠移植动脉硬化的发生并强烈抑制了移植动脉硬化的进展。
Background. Although activated platelets influence inflammation by intraplatelet mediators in transplantation, their mechanism of involvement in the progression of transplant arteriosclerosis has not yet been elucidated. We, therefore, investigated this question using P2Y12 receptor knockout (KO) mice, in which platelets cannot be aggregated by adenosine diphosphate stimulation. Methods. Carotid arteries from 129X1 mice were orthotopically transplanted into wild-type or KO mice in a minor antigen(s)-mismatched strain combination. No immunosuppression was used. Grafts were harvested at 7, 14, 28, and 56 days after transplantation for morphometry and immunohistology. Fluorescence-activated cell sorting and quantitative real-time reverse-transcriptase polymerase chain reaction were performed at 7 and 14 days after transplantation. Results. The intima/media ratio of grafts in KO mice was significantly reduced compared with wild-type mice at 14, 28, and 56 days after transplantation. Fluorescence-activated cell sorting analysis showed a significant reduction of platelet CD154 expression and platelet-leukocyte aggregates in KO mice at 14 days after transplantation. Additionally, levels of intercellular adhesion molecule-1 and CD40 mRNA, and numbers of intercellular adhesion molecule-1- or CD40-positive cells in the grafts were lower in KO mice at 7 and 14 days after transplantation. These reductions resulted in a significant attenuation of CD45-positive leukocytes adhering to the graft vessel wall in KO mice at 14 days after transplantation. Conclusion. Diminished platelet function by P2Y12 receptor deficiency attenuates initiation and strongly inhibits progression of transplant arteriosclerosis in mice by diminishing adhesion molecule expression and leukocyte accumulation in the grafts during the early phase after transplantation.