Article
Tetrahydrobiopterin as a novel therapeutic agent in the prevention of chronic allograft vasculopathy
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Authors
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Rupert Oberhuber
- Medical University Innsbruck, Austria, Center of Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck
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David Bernhard
- Medical University Vienna, Austria, Department of Cardiac and Thoracic Surgery, Wien
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Barbara Messner
- Medical University Vienna, Austria, Department of Cardiac and Thoracic Surgery, Wien
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Benno Cardini
- Medical University Innsbruck, Austria, Center of Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck
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Gregor Riede
- Medical University Innsbruck, Austria, Center of Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck
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Walter Mark
- Medical University Innsbruck, Austria, Center of Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck
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Christina Steger
- Medical University Innsbruck, Austria, Center of Operative Medicine, Department of Heart Surgery, Innsbruck
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Gerald Brandacher
- Medical University Innsbruck, Austria, Center of Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck
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Johann Pratschke
- Medical University Innsbruck, Austria, Center of Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck
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Katrin Watschinger
- Medical University Innsbruck, Austria, Division of Biological Chemistry, Biocenter, Innsbruck
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Werner Ernst
- Medical University Innsbruck, Austria, Division of Biological Chemistry, Biocenter, Innsbruck
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Manuel Maglione
- Medical University Innsbruck, Austria, Center of Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck
| Published: | May 20, 2011 |
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Outline
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Introduction: Chronic rejection characterized by allograft vasculopathy is still a major obstacle to long term graft survival. Among different triggers the outstanding non-immunologic factor associated with chronic allograft vasculopathy (CAV) is ischemia reperfusion injury. Recently we were able to show that tetrahydrobiopterin (H4B), the essential cofactor for nitric oxide synthases significantly reduces ischemia reperfusion injury (IRI). Herein we analyzed whether H4B supplementation may also attenuate CAV by prevention of IRI.
Materials and methods: A fully MHC mismatched (Balbc to C57bl6) mouse heterotopic cervical aortic transplantation model was used. Transplanted grafts were subjected to 24 h prolonged cold ischemia time (CIT) and to 45 min warm ischemia time. Donor animals received either H4B (50 mg/kg/BW) prior to organ retrieval or saline. Naive aortas served as controls. Aortic grafts were retrieved for further analysis 10 h and 4 weeks following reperfusion, respectively. Glutathion (GSH) tissue level measurements as well as HSP-70 western blot were performed to assess IRI-related tissue damage (10 h following reperfusion). Quantification of intimal hyperplasia as CAV-indicator was done by histology (hematoxylin and eosin) 4 weeks following reperfusion.
Results: Prolonged CIT resulted in a significant reduction of GSH tissue levels when compared to control animals (p<0.05). In parallel HSP-70 expression was elevated (p<0.05). Furthermore, supplementation of H4B resulted in significant restoration of GSH tissue levels, as well as in a reduction of HSP-70 expression (p<0.05). Histopathology at 4 weeks after transplantation revealed CAV characterized by prominent intimal hyperplasia in the untreated group. In contrast pretreatment with H4B lead to a significant reduction of intimal hyperplasia (p<0.001).
Conclusion: These data suggest that the degree of IRI strongly correlates with CAV development and that donor pre-treatment with H4B might therefore represent a novel agent in transplantation to attenuate CAV
