The role of fibrinolytic genes and proteins in the development of allograft vascular disease

Academic Article

Abstract

  • Background: We have previously shown that lack of plasminogen activator inhibitor-1 (PAI-1) expression in donor tissue greatly increases intimal proliferation (IP) after allogeneic transplantation. We sought to determine the relative role of PAI-1 and other fibrinolytic proteins in the development of IP. Methods: We used an abdominal aortic transplant model in mice to investigate IP in 3 groups of 6 recipients. In the isograft group, CBA/J strain mice were donors and recipients, donors for allograft group were C57BL/6J mice, and for the allograft/knockout group, C57BL/6J PAI-1 knockout mice. All groups received weekly injections of anti-CD8/CD4 monoclonal antibodies. IP was calculated at 50 days, and sections were analyzed for fibrinolytic proteins, messenger RNA (mRNA) and PAI-1 activity using immunohistochemistry (IHC), in situ hybridization (ISH), reverse transcription-polymerase chain reaction (RT-PCR), and Western blot analysis. Results: Significantly more IP developed in the allograft/knockout group vs the isograft (p < 0.001) and the allograft groups (p = 0.003). There was marked intimal expression of tissue plasminogen activator (tPA), urokinase PA (uPA), and uPA receptor (uPAR) proteins and mRNA in the allograft and allograft/knockout groups vs the isograft group. Allografts also showed significant intimal staining for PAI-1 protein and mRNA. RT-PCR demonstrated a stepwise increase in profibrinolytic protein mRNA from isograft to allograft to allograft/knockout groups, particularly uPA (p = 0.02) and uPAR (p = 0.016). Western blot data showed complementary findings. PAI-1 activity was persistently present in isograft and allograft animals, only. Intimas in allograft and allograft/knockout groups were primarily smooth muscle cells. Conclusions: PAI-1 reduces IP by limiting smooth muscle cell activity, with little change in matrix composition likely by modulating profibrinolytic protein expression. © 2011 International Society for Heart and Lung Transplantation.
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    Author List

  • Benza RL; Passineau MJ; Anderson PG; Barchue JP; George JF
  • Start Page

  • 935
  • End Page

  • 944
  • Volume

  • 30
  • Issue

  • 8