title: Spinal Cord Ischemia-Reperfusion Injury Induces Erythropoietin Receptor Expression.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors: Department of Surgery, University of Colorado Denver, Denver, Colorado. Electronic address: lisa.foley@ucdenver.edu.
authors: Lisa S
authors: LS
authors: Foley
authors: Department of Surgery, University of Colorado Denver, Denver, Colorado.
authors: David A
authors: DA
authors: Fullerton
authors: Department of Surgery, University of Colorado Denver, Denver, Colorado.
authors: Daine T
authors: DT
authors: Bennett
authors: Department of Surgery, University of Colorado Denver, Denver, Colorado.
authors: Kirsten A
authors: KA
authors: Freeman
authors: Department of Surgery, University of Colorado Denver, Denver, Colorado.
authors: Joshua
authors: J
authors: Mares
authors: Department of Surgery, University of Colorado Denver, Denver, Colorado.
authors: Marshall T
authors: MT
authors: Bell
authors: Department of Surgery, University of Colorado Denver, Denver, Colorado.
authors: Joseph C
authors: JC
authors: Cleveland
authors: Department of Surgery, University of Colorado Denver, Denver, Colorado.
authors: Michael J
authors: MJ
authors: Weyant
authors: Department of Surgery, University of Colorado Denver, Denver, Colorado.
authors: Xianzhong
authors: X
authors: Meng
authors: Department of Anesthesiology, University of Colorado Denver, Denver, Colorado.
authors: Ferenc
authors: F
authors: Puskas
authors: Department of Surgery, University of Colorado Denver, Denver, Colorado.
authors: T Brett
authors: TB
authors: Reece
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017467:Receptors, Erythropoietin / Q000096:biosynthesis*; D015427:Reperfusion Injury / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000502:physiology; D013116:Spinal Cord / Q000098:blood supply*; D020760:Spinal Cord Ischemia / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D017467:Receptors, Erythropoietin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse