Carbon monoxide rescues heme oxygenase-1-deficient mice from arterial thrombosis in allogeneic aortic transplantation.
Heme oxygenase-1 (HO-1) catalyzes the conversion of heme into carbon monoxide (CO), iron, and biliverdin. In preliminary studies, we observed that the absence of HO-1 in aortic allograft recipients resulted in 100% mortality within 4 days due to arterial thrombosis. In contrast, recipients normally expressing HO-1 showed 100% graft patency and survival for more than 56 days. Abdominal aortic transplants were performed using Balb/cJ mice as donors and either HO-1(+/+) or HO-1(-/-) (C57BL/6xFVB) mice as recipients. Light and electron microscopy revealed extensive platelet-rich thrombi along the entire length of the graft in HO-1(-/-) recipients at 24 hours. Treatment of recipients with CORM-2, a CO-releasing molecule (10 mg/kg of body weight intravenously), 1 hour prior and 1, 3, and 6 days after transplantation, significantly improved survival (62% at >56 days, P < 0.001) compared with HO-1(-/-) recipients treated with inactive CORM-2 (median survival 1 day). Histological analyses revealed that CO treatment markedly reduced platelet aggregation within the graft. Adoptive transfer of wild-type platelets to HO-1(-/-) recipients also conferred protection and increased survival. Aortic transplants from either HO-1(-/-) or HO-1(+/+) C57BL/6 donors into HO-1(+/+) (Balb/cJ) mice did not develop arterial thrombosis, surviving more than 56 days. These studies demonstrate an important role for systemic HO-1/CO for protection against vascular arterial thrombosis in murine aortic allotransplantation.
Chen
Bo
B
Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Guo
Lingling
L
Fan
Chunlan
C
Bolisetty
Subhashini
S
Joseph
Reny
R
Wright
Marcienne M
MM
Agarwal
Anupam
A
George
James F
JF
D000818:Animals; D001011:Aorta / Q000473:pathology / Q000637:transplantation*; D015153:Blotting, Western; D002248:Carbon Monoxide / Q000378:metabolism*; D006085:Graft Survival; D051547:Heme Oxygenase-1 / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D046529:Microscopy, Electron, Transmission; D016377:Organ Transplantation / Q000009:adverse effects*; D013927:Thrombosis / Q000209:etiology / Q000378:metabolism*; D014184:Transplantation, Homologous
D002248:Carbon Monoxide; D051547:Heme Oxygenase-1