信号传导蛋白和转录激活物3参与调节大鼠异种心脏移植延迟性排斥反应

Involvement of signal transducer and activator of transcription 3 in delayed xenograft rejection in mice-torats cardiac transplantation as a regulator

目的探讨信号传导蛋白和转录激活物3（STAT3）在异种移植延迟性排斥反应（DxR）中的作用。方法构建小鼠供大鼠异种心脏移植模型，实验分为5组，空白对照组、移植组、DPP组[移植后给予STAT3磷酸化抑制剂5，15-Diphenylporphyrin（DPP）]、环孢素A（CsA）组（移植后给予CsA）、DPP＋csA组（移植后给予DPP＋CsA），采用免疫组织化学及蛋白质印迹法检测心肌组织中磷酸化STAT3（p-STAT3）的表达，采用实时荧光定量聚合酶链反应检测心肌组织中STAT3下游靶基因的表达，观察各组移植心的存活时间。结果随着移植时间的延长，移植心肌组织中p-STAT3的表达明显增加（P〈0．05）。与移植组比较，DPP及CsA处理可明显抑制p-STAT3的表达，延长移植心的存活时间（P〈0．05），二者具有协同效应；DPP及CsA处理可显著抑制STA T3靶基因Bcl—xl、Bcl-2、Cyclin D1、C-myc及血管内皮生长因子（VEGF）的表达（P〈0．05），DPP＋CsA处理可进一步抑制各靶基因表达。结论STAT3在异种移植心脏中持续活化，可能通过上调Bcl—x1、Bcb2、cyclinD1、C-myc及VEGF等相关基因表达，促进血管内皮细胞的增殖，并抑制其凋亡，在内皮细胞激活及DXR的发生中发挥重要作用。

Objective To evaluate the roles of signal transducer and activator of transcription 3 （STAT3） played in delayed xenograft rejection. Method Mice-to-rats cardiac xenograft model was established and recipients were administrated by inhibitor of phosphorylation of STAT3, 5, 15- Diphenylporphyrin（DPP）, and immunosuppressive agent, ciclosporin A （CsA） alone or both. The survival of graft was analyzed. Immunohistochemistry and immunoblotting were utilized to detect the phosphorylated STAT3 （p STAT3）, and real-time polymerase chain reaction was used to assess STAT3-targeted genes in grafts. Result The expression of p-STAT3 was increased significantly with the prolonged survival in grafts （P 〈 0. 05）. Administration of DPP and CsA both significantly prolonged survival of the grafts （P〈0. 05）, and decreased the expressions of STAT3-targeted genes including Bcl-xl, Bcl-2, Cyclin D1, C-myc and VEGF （P 〈 0. 05 ）. DPP and CsA exerted the synergistic dfects. Conclusion STAT3, which is persistently activated in cardiac xenografts, probably up-regulates downstream genes to promote proliferation and to inhibit apoptosis of endothelial cells, leading to the activation of endothelial cells and delayed xenograft rejection.