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Originally published online as doi:10.2353/ajpath.2009.081033 on June 4, 2009

Published online before print June 4, 2009
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(American Journal of Pathology. 2009;175:422-429.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.081033

Carbon Monoxide Rescues Heme Oxygenase-1-Deficient Mice from Arterial Thrombosis in Allogeneic Aortic Transplantation

Bo Chen*, Lingling Guo{dagger}, Chunlan Fan*, Subhashini Bolisetty*, Reny Joseph*, Marcienne M. Wright*, Anupam Agarwal* and James F. George{dagger}

From the Department of Medicine,* Nephrology Research and Training Center, and the Department of Surgery,{dagger} University of Alabama at Birmingham, Birmingham, Alabama

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.


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