Cytochrome p450 2C enzymes contribute to peritransplant ischemic injury and cardiac allograft vasculopathy.
Peritransplant ischemia and reperfusion (I/R) injury contributes to posttransplant vascular dysfunction and cardiac allograft vasculopathy (CAV). We have previously shown that cytochrome p450 (CYP) 2C inhibition significantly reduces I/R-induced myocardial infarction and postischemic vascular dysfunction. In the latter study, pretreatment with sulfaphenazole (SP), a specific inhibitor of CYP 2C, restored postischemic NO-mediated, endothelium-dependent vasodilation and reduced vascular superoxide production. Given the association between I/R injury, early vascular dysfunction and CAV, we hypothesized that CYP 2C may also contribute to the onset of CAV. Lewis-to-Fisher rat heterotopic heart transplants were performed. Donors and recipients were treated with 5 mg/kg SP or vehicle control 1 h prior to surgery. SP did not affect posttransplant morbidity, mortality or weight gain. Coronary blood vessels from rats treated with SP exhibited significantly reduced luminal narrowing and demonstrated a corresponding decrease in smooth muscle cell (SMC) proliferation compared to controls. SP did not reduce diffuse, focal, epicardial, endocardial or perivascular immune infiltration nor did it significantly alter TUNEL positivity in myocardial, endothelial or SMC populations. In conclusion, CYP 2C contributes to SMC proliferation CAV without affecting general immune infiltration.
James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul's Hospital, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada. dgranville@mrl.ubc.ca
A L
AL
Hunter
A
A
Kerjner
K J
KJ
Mueller
B M
BM
McManus
D J
DJ
Granville
D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects*; D003331:Coronary Vessels; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D016027:Heart Transplantation; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000517:prevention & control*; D051381:Rats; D011917:Rats, Inbred Lew; D013426:Sulfaphenazole / Q000008:administration & dosage; D014184:Transplantation, Homologous
D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; C400322:cytochrome P-450 CYP2C subfamily; D013426:Sulfaphenazole; D003577:Cytochrome P-450 Enzyme System