Foley Lisa S, Fullerton David A, Bennett Daine T, Freeman Kirsten A, Mares Joshua, Bell Marshall T, Cleveland Joseph C, Weyant Michael J, Meng Xianzhong, Puskas Ferenc, Reece T Brett
Department of Surgery, University of Colorado Denver, Denver, Colorado.
Department of Surgery, University of Colorado Denver, Denver, Colorado.
Ann Thorac Surg. 2015 Jul;100(1):41-6; discussion 46. doi: 10.1016/j.athoracsur.2015.01.027. Epub 2015 Apr 9.
Paraplegia remains a devastating complication of aortic surgery, occurring in up to 20% of complex thoracoabdominal repairs. Erythropoietin (EPO) attenuates this injury in models of spinal cord ischemia. Upregulation of the beta-common receptor (βcR) subunit of the EPO receptor is associated with reduced damage in murine models of neural injury. This receptor activates anti-apoptotic pathways including signaling transducer and activator of transcription 3 (STAT3). We hypothesized that spinal cord ischemia-reperfusion injury upregulates the βcR subunit with a subsequent increase in activated STAT3.
Adult male C57/BL6 mice received an intraperitoneal injection of 0.5 mL of EPO (10 U/kg) or 0.9% saline after induction of anesthesia. Spinal cord ischemia was induced through sternotomy and 4-minute thoracic aortic cross-clamp. Sham mice underwent sternotomy without cross-clamp placement. Four groups were studied: ischemic and sham groups, each with and without EPO treatment. After 4 hours of reperfusion, spinal cords were harvested and homogenized. The βcR subunit expression and STAT3 activation were evaluated by immunoblot.
Ischemia reperfusion increased βcR subunit expression in spinal cords of ischemia + saline and ischemia + EPO mice compared with shams (3.4 ± 1.39 vs 1.31 ± 0.3, p = 0.01 and 3.80 ± 0.58 vs 1.56 ± 0.32, p = 0.01). Additionally, both ischemic groups demonstrated increased STAT3 activation compared with shams (1.35 ± 0.14 vs 1.09 ± 0.07, p = 0.01 and 1.66 ± 0.35 vs 1.08 ± 0.17, p = 0.02).
Ischemia-reperfusion injury induces EPO receptor βcR subunit expression and early downstream anti-apoptotic signaling through STAT3 activation. Further investigation into the role of the βcR subunit is warranted to determine tissue protective functions of EPO. Elucidation of mechanisms involved in spinal cord protection is essential for reducing delayed paraplegia.
截瘫仍然是主动脉手术的一种灾难性并发症，在复杂的胸腹主动脉修复手术中发生率高达20%。促红细胞生成素（EPO）在脊髓缺血模型中可减轻这种损伤。EPO受体的β共同受体（βcR）亚基上调与神经损伤小鼠模型中的损伤减轻有关。该受体激活包括信号转导和转录激活因子3（STAT3）在内的抗凋亡途径。我们推测脊髓缺血再灌注损伤会使βcR亚基上调，随后激活的STAT3增加。
成年雄性C57/BL6小鼠在麻醉诱导后腹腔注射0.5 mL EPO（10 U/kg）或0.9%生理盐水。通过胸骨切开术和4分钟的胸主动脉交叉夹闭诱导脊髓缺血。假手术小鼠仅行胸骨切开术，不放置交叉夹。研究四组：缺血组和假手术组，每组又分为接受EPO治疗和未接受EPO治疗。再灌注4小时后，取出脊髓并匀浆。通过免疫印迹法评估βcR亚基表达和STAT3激活情况。
与假手术组相比，缺血再灌注使缺血 + 生理盐水组和缺血 + EPO组小鼠脊髓中的βcR亚基表达增加（分别为3.4 ± 1.39 vs 1.31 ± 0.3，p = 0.01；3.80 ± 0.58 vs 1.56 ± 0.32，p = 0.01）。此外，与假手术组相比，两个缺血组的STAT3激活均增加（分别为1.35 ± 0.14 vs 1.09 ± 0.07，p = 0.01；1.66 ± 0.35 vs 1.08 ± 0.17，p = 0.02）。
缺血再灌注损伤通过激活STAT3诱导EPO受体βcR亚基表达及早期下游抗凋亡信号。有必要进一步研究βcR亚基的作用，以确定EPO的组织保护功能。阐明脊髓保护机制对于减少延迟性截瘫至关重要。
