Superoxide dismutase mimetic m40401 reduces ischemia-reperfusion injury and graft coronary artery disease in rodent cardiac allografts.
BACKGROUND
The oxidative stress associated with ischemia-reperfusion (I/R) of cardiac allografts leads to production of injurious cytokines and expression of proinflammatory adhesion molecules. This is one of the most important alloantigen-independent factors associated with graft coronary artery disease (GCAD). M40401 is a newly developed cell permeable superoxide dismutase mimetic, which has been shown to scavenge superoxide anion with highly specific and enhanced catalytic activity. We hypothesized that M40401 would exert a protective effect in I/R injury of cardiac allografts and ameliorate the progression of GCAD.


METHODS
Recipient ACI rats were pretreated with M40401 or vehicle control. PVG donor hearts were heterotopically transplanted into the abdomen of ACI recipients. Cardiac allografts were analyzed for adhesion molecule mRNA expression and tumor necrosis factor-alpha expression after 4 hr of reperfusion. Neutrophil infiltration was detected by myeloperoxidase activity. Intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and endothelial leukocyte adhesion molecule-1 mRNA were detected by reverse-transcriptase polymerase chain reaction. Immunohistochemical analysis of adhesion molecule expression was also performed. Additional grafts were procured 90 days after transplantation and assessed for the development of GCAD by computer-assisted image analysis.


RESULTS
In the M40401-treated group, adhesion molecule expression was significantly less than in the vehicle control group. Treated grafts also had lower myeloperoxidase activity and tumor necrosis factor-alpha concentration compared with controls. Neointimal proliferation and intima to media ratios in M40401-treated allografts were significantly decreased compared with controls.


CONCLUSIONS
Selective removal of superoxide anion by M40401 results in inhibition of I/R injury. Furthermore, M40401 treatment decreases the development of oxidative stress-associated GCAD. This treatment strategy may have broad cardioprotective applications for all cardiac operations in addition to cardiac transplantation.
Murata
Seiichiro
S
Department of Cardiothoracic Surgery, Stanford University Medical Center, Stanford, CA 94305, USA.
Miniati
Douglas N
DN
Kown
Murray H
MH
Koransky
Mark L
ML
Lijkwan
Maarten A
MA
Balsam
Leora B
LB
Robbins
Robert C
RC
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003327:Coronary Disease / Q000209:etiology* / Q000473:pathology*; D016027:Heart Transplantation / Q000009:adverse effects*; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D017202:Myocardial Ischemia / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009942:Organometallic Compounds / Q000494:pharmacology*; D051381:Rats; D011912:Rats, Inbred ACI; D011919:Rats, Inbred Strains; D013482:Superoxide Dismutase / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D002316:Cardiotonic Agents; C426066:M40401; D016328:NF-kappa B; D009942:Organometallic Compounds; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D013482:Superoxide Dismutase