Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado, Aurora, Colorado.
Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado, Aurora, Colorado.
Ann Thorac Surg. 2018 Dec;106(6):1751-1758. doi: 10.1016/j.athoracsur.2018.07.022. Epub 2018 Sep 5.
Paraplegia remains a devastating complication of thoracoabdominal aortic intervention. Metabolic stress induces expression of beta common receptor subunit of erythropoietin (EPO) receptor (βcR) to exert a neuroprotective effect in spinal cord ischemia reperfusion injury (SCIR). Diazoxide (DZ) has been shown to induce ischemic tolerance. We previously reported that DZ upregulated βcR expression and enhanced the neuroprotective effects of EPO through the upregulation of βcR. We hypothesize that βcR expression induced by DZ before ischemia amplifies the antiapoptotic effects of EPO in a murine model of SCIR.
Experimental groups included phosphate-buffered saline (PBS) pretreatment + PBS immediately before the operation, PBS+EPO, DZ+PBS, DZ+EPO, and sham. Spinal cord ischemia was induced by a 4-minute thoracic aortic cross-clamp. Functional scoring (Basso Mouse Score) was done at 12-hour intervals for 48 hours. Spinal cords were harvested for histologic analysis, and antiapoptotic factors (caspase 3, 8, and 9, B-cell lymphoma-2, and neuroglobin) were evaluated by Western blot analysis.
The motor function of DZ+EPO group was significantly preserved compared with all other groups. The levels of cleaved caspase 8 and 3 in DZ+EPO were significantly lower than in the other groups. Mice treated with DZ+EPO had significantly fewer terminal deoxynucleotide transferase-mediated deoxy uridine triphosphate nick-end labeling-positive cells than other groups.
Optimized upregulation of βcR by DZ can increase the extrinsic antiapoptotic effects of EPO. Better understanding of this synergetic mechanism may serve to help prevent ischemic complications caused by aortic intervention.
截瘫仍然是胸主动脉腹主动脉介入治疗的一种毁灭性并发症。代谢应激诱导促红细胞生成素（EPO）受体的β共同受体亚单位（βcR）的表达，从而在脊髓缺血再灌注损伤（SCIR）中发挥神经保护作用。二氮嗪（DZ）已被证明可诱导缺血耐受。我们之前报道过，DZ 通过上调βcR 来上调 βcR 的表达，从而增强 EPO 的神经保护作用。我们假设，DZ 在缺血前诱导的 βcR 表达可增强 EPO 在 SCIR 小鼠模型中的抗凋亡作用。
实验组包括磷酸盐缓冲盐水（PBS）预处理+手术前即刻 PBS、PBS+EPO、DZ+PBS、DZ+EPO 和假手术组。通过 4 分钟的胸主动脉夹闭诱导脊髓缺血。在 48 小时内每隔 12 小时进行功能评分（Basso 小鼠评分）。收获脊髓进行组织学分析，并通过 Western blot 分析评估抗凋亡因子（半胱天冬酶 3、8 和 9、B 细胞淋巴瘤-2 和神经球蛋白）。
与其他所有组相比，DZ+EPO 组的运动功能明显得到保留。DZ+EPO 中的裂解半胱天冬酶 8 和 3 水平明显低于其他组。与其他组相比，DZ+EPO 处理的小鼠末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记阳性细胞明显减少。
DZ 优化的βcR 上调可增加 EPO 的外在抗凋亡作用。更好地理解这种协同机制可能有助于预防主动脉介入引起的缺血并发症。
