Dysferlin mediates the cytoprotective effects of TRAF2 following myocardial ischemia reperfusion injury.
Dysferlin mediates the cytoprotective effects of TRAF2 following myocardial ischemia reperfusion injury.
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DOI：
10.1161/jaha.113.000662
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发表时间：
2014-02-26
影响因子：
5.4
通讯作者：
Mann DL
中科院分区：
文献类型：
--
作者：
Tzeng HP;Evans S;Gao F;Chambers K;Topkara VK;Sivasubramanian N;Barger PM;Mann DL
我们已经证明，肿瘤坏死因子受体相关因子2(TRAF2)是肿瘤坏死因子受体1和2共同的支架蛋白，在心脏中具有细胞保护作用。然而，TRAF2的细胞保护作用机制尚不清楚。心脏受限低水平TRAF2高表达小鼠(MHC-TRAF2LC)和显性阴性TRAF2小鼠(MHC-TRAF2DN)采用朗宁多夫装置造成缺血(30分钟)再灌注(60分钟)损伤(I/R)。MHC-TRAF2LC小鼠对I/R损伤有明显的保护作用，与LM相比，I/R后左室压(LV)显著增加27%，而TRAF2信号受损的小鼠左室压显著降低38%，肌酸激酶(CK)释放≈增加41%，≈摄取伊文思蓝增加52%。MHC-TRAF2LC和MHC-TRAF2DN小鼠的转录图谱表明，钙触发的胞外膜修复蛋白dyferlin是TRAF2细胞保护作用的潜在细胞保护基因。与野生型小鼠相比，缺乏deferlin的小鼠在I/R后左室形成压显著降低39%，CK释放增加20%，伊文斯蓝摄取增加29%，因此在MHC-TRAF2DN小鼠中表现出对组织损伤的反应。此外，在干扰素缺失的背景上培育MHC-TRAF2LC显著减弱了TRAF2在I/R损伤后的细胞保护作用。研究表明，钙离子触发的胞外膜修复蛋白dyferlin是TRAF2介导的信号在I/R损伤后的细胞保护作用所必需的。
We have demonstrated that tumor necrosis factor (TNF) receptor‐associated factor 2 (TRAF2), a scaffolding protein common to TNF receptors 1 and 2, confers cytoprotection in the heart. However, the mechanisms for the cytoprotective effects of TRAF2 are not known. Mice with cardiac‐restricted overexpression of low levels of TRAF2 (MHC‐TRAF2LC) and a dominant negative TRAF2 (MHC‐TRAF2DN) were subjected to ischemia (30‐minute) reperfusion (60‐minute) injury (I/R), using a Langendorff apparatus. MHC‐TRAF2LC mice were protected against I/R injury as shown by a significant ≈27% greater left ventricular (LV) developed pressure after I/R, whereas mice with impaired TRAF2 signaling had a significantly ≈38% lower LV developed pressure, a ≈41% greater creatine kinase (CK) release, and ≈52% greater Evans blue dye uptake after I/R, compared to LM. Transcriptional profiling of MHC‐TRAF2LC and MHC‐TRAF2DN mice identified a calcium‐triggered exocytotic membrane repair protein, dysferlin, as a potential cytoprotective gene responsible for the cytoprotective effects of TRAF2. Mice lacking dysferlin had a significant ≈39% lower LV developed pressure, a ≈20% greater CK release, and ≈29% greater Evans blue dye uptake after I/R, compared to wild‐type mice, thus phenocopying the response to tissue injury in the MHC‐TRAF2DN mice. Moreover, breeding MHC‐TRAF2LC onto a dysferlin‐null background significantly attenuated the cytoprotective effects of TRAF2 after I/R injury. The study shows that dysferlin, a calcium‐triggered exocytotic membrane repair protein, is required for the cytoprotective effects of TRAF2‐mediated signaling after I/R injury.