Mitochondrial permeability regulates cardiac endothelial cell necroptosis and cardiac allograft rejection
Mitochondrial permeability regulates cardiac endothelial cell necroptosis and cardiac allograft rejection
复制标题
DOI：
10.1111/ajt.15112
复制
发表时间：
2019-03-01
影响因子：
8.8
通讯作者：
Zhang, Zhu-Xu
中科院分区：
文献类型：
--
作者：
Gan, Ingrid;Jiang, Jifu;Zhang, Zhu-Xu
移植总是与程序性细胞死亡相关，包括细胞凋亡和坏死，导致移植物功能延迟和器官排斥。我们已经证明了坏死下垂对小鼠微血管内皮细胞（MVEC）死亡和移植排斥反应的贡献。器官损伤导致线粒体通透性过渡孔（mPTPs）打开，从而触发凋亡分子释放，最终导致细胞死亡。mPTPs在坏死坏死途径中的作用仍有争议；重要的是，它们在移植排斥反应中的作用尚不清楚。在本研究中，肿瘤坏死因子- α触发mvec发生受体相互作用蛋白激酶家族（RIPK1/3）依赖性坏死上睑坏死。有趣的是，抑制mPTP开放也可以抑制坏死细胞死亡。亲环蛋白d （Cyp-D）是mptp的关键调节因子。抑制和缺乏Cyp-D均可保护mvec免于坏死性坏死（n = 3, P < 0.00001）。此外，cypd的抑制减弱了ripk3下游混合谱系激酶结构域样蛋白的磷酸化。在体内，与野生型移植物相比，同种异体BALB/c小鼠移植后cypd缺陷心脏移植物的存活时间更长（n = 7, P < 0.0001）。我们的研究结果表明mptp可能是心脏移植物坏死下垂的重要机制介质。通过抑制mptp调节分子Cyp-D靶向细胞死亡来预防心脏移植排斥反应具有治疗潜力。
Transplantation is invariably associated with programmed cell death including apoptosis and necrosis, resulting in delayed graft function and organ rejection. We have demonstrated the contribution of necroptosis to mouse microvascular endothelial cell (MVEC) death and transplant rejection. Organ injury results in the opening of mitochondrial permeability transition pores (mPTPs), which can trigger apoptotic molecules release that ultimately results in cell death. The effect of mPTPs in the necroptotic pathway remains controversial; importantly, their role in transplant rejection is not clear. In this study, tumor necrosis factor-alpha triggered MVECs to undergo receptor-interacting protein kinase family (RIPK1/3)-dependent necroptosis. Interestingly, inhibition of mPTP opening could also inhibit necroptotic cell death. Cyclophilin-D (Cyp-D) is a key regulator of the mPTPs. Both inhibition and deficiency of Cyp-D protected MVECs from necroptosis (n = 3, P < .00001). Additionally, inhibition of Cyp-D attenuated RIPK3-downstream mixed-lineage kinase domain-like protein phosphorylation. In vivo, Cyp-D-deficient cardiac grafts showed prolonged survival in allogeneic BALB/c mice posttransplant compared with wild-type grafts (n = 7, P < .0001). Our study results suggest that the mPTPs may be important mechanistic mediators of necroptosis in cardiac grafts. There is therapeutic potential in targeting cell death via inhibition of the mPTP-regulating molecule Cyp-D to prevent cardiac graft rejection.