Carbon monoxide rescues heme oxygenase-1-deficient mice from arterial thrombosis in allogeneic aortic transplantation.

Academic Article

Abstract

  • 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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    Keywords

  • Animals, Aorta, Blotting, Western, Carbon Monoxide, Graft Survival, Heme Oxygenase-1, Mice, Microscopy, Electron, Transmission, Organ Transplantation, Thrombosis, Transplantation, Homologous
  • Digital Object Identifier (doi)

    Authorlist

  • Chen B; Guo L; Fan C; Bolisetty S; Joseph R; Wright MM; Agarwal A; George JF
  • Start Page

  • 422
  • End Page

  • 429
  • Volume

  • 175
  • Issue

  • 1