Overexpression of human copper/zinc superoxide dismutase (SOD1) suppresses ischemia-reperfusion injury and subsequent development of graft coronary artery disease in murine cardiac grafts

Circulation. 2004 Sep 14;110(11 Suppl 1):II200-6. doi: 10.1161/01.CIR.0000138390.81640.54.

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.

Methods and 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Caspase 3
  • Caspase 9
  • Caspases / metabolism
  • Chemokine CCL2 / biosynthesis
  • Coronary Disease / etiology
  • Coronary Disease / prevention & control*
  • Drug Evaluation, Preclinical
  • Fas Ligand Protein
  • Graft Rejection / etiology
  • Graft Rejection / prevention & control*
  • Heart Transplantation*
  • Humans
  • Inflammation / prevention & control
  • Membrane Glycoproteins / biosynthesis
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myocardial Contraction
  • Myocardial Ischemia / complications
  • Myocardial Ischemia / prevention & control*
  • Myocardial Reperfusion Injury / complications
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / pathology
  • Peroxidase / analysis
  • Postoperative Complications / etiology
  • Postoperative Complications / prevention & control*
  • Recombinant Fusion Proteins / physiology
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / physiology*
  • Superoxide Dismutase-1
  • Superoxides / metabolism
  • Transplantation, Heterotopic
  • Transplantation, Homologous
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Ccl2 protein, mouse
  • Chemokine CCL2
  • FASLG protein, human
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Membrane Glycoproteins
  • Recombinant Fusion Proteins
  • SOD1 protein, human
  • Tumor Necrosis Factor-alpha
  • Superoxides
  • Peroxidase
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • CASP3 protein, human
  • CASP9 protein, human
  • Casp3 protein, mouse
  • Casp9 protein, mouse
  • Caspase 3
  • Caspase 9
  • Caspases