title: Overexpression of human copper/zinc superoxide dismutase (SOD1) suppresses ischemia-reperfusion injury and subsequent development of graft coronary artery disease in murine cardiac grafts.
abstract: BACKGROUND
  Ischemia-reperfusion injury is an important risk factor for graft coronary artery disease (GCAD). We hypothesized that overexpression of SOD1 in donor hearts would suppress ischemia-reperfusion injury and thereby reduce GCAD.
  
  
  RESULTS
  In one series, donor hearts of C57BL/6 (H-2b) transgenic mice overexpressing human SOD1 or C57BL/6 wild-type mice were heterotopically transplanted into C57BL/6 recipients and procured after 4 hours of reperfusion (n=6 each). Superoxide, TNF-alpha, and MCP-1/CCL2 production were significantly reduced in the SOD1 transgenic donor heart recipients, and graft injury determined by serum CPK-MB levels was significantly decreased. Cardiomyocyte apoptosis and caspase-3 and caspase-9 activities were significantly decreased in these recipients; caspase-8 activity was unchanged. Fas ligand but not Fas expression was also reduced. In a second series, transgenic and wild-type hearts were transplanted into C-H-2bm12KhEg (H-2bm12) recipients, and then procured on day 56 (n=7 each). Cardiac graft beating was significantly better in the SOD1 transgenic donor heart recipients on days 28, 42, and 56 (but not day 14). Significant reduction in luminal narrowing, the intima/media ratio, and the percentage of diseased vessels was seen in the SOD1 transgenic donor heart recipients, and MCP-1/CCL2, ICAM-1, and VCAM-1 production were significantly reduced.
  
  
  CONCLUSIONS
  Overexpression of SOD1 attenuates both apoptosis and the inflammatory response during ischemia-reperfusion injury and therefore mitigates against the subsequent development of GCAD.
authors.affiliation: Department of Cardiothoracic Surgery, Stanford University Medical Center, Stanford, Calif, USA. masashi@omiya.jichi.ac.jp
authors.forename: Masashi
authors.initials: M
authors.lastname: Tanaka
authors.forename: Golnaz K
authors.initials: GK
authors.lastname: Mokhtari
authors.forename: Raya D
authors.initials: RD
authors.lastname: Terry
authors.forename: Leora B
authors.initials: LB
authors.lastname: Balsam
authors.forename: Keun-Ho
authors.initials: KH
authors.lastname: Lee
authors.forename: Theo
authors.initials: T
authors.lastname: Kofidis
authors.forename: Philip S
authors.initials: PS
authors.lastname: Tsao
authors.forename: Robert C
authors.initials: RC
authors.lastname: Robbins
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D018932:Chemokine CCL2 / Q000096:biosynthesis; D003327:Coronary Disease / Q000209:etiology / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D053222:Fas Ligand Protein; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control*; D016027:Heart Transplantation; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000150:complications / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D009195:Peroxidase / Q000032:analysis; D011183:Postoperative Complications / Q000209:etiology / Q000517:prevention & control*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013482:Superoxide Dismutase / Q000235:genetics / Q000502:physiology*; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; C000606290:SOD1 protein, human; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D009195:Peroxidase; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases