Donor Heart Treatment With COMP-Ang1 Limits Ischemia-Reperfusion Injury and Rejection of Cardiac Allografts.
The major cause of death during the first year after heart transplantation is primary graft dysfunction due to preservation and ischemia-reperfusion injury (IRI). Angiopoietin-1 is a Tie2 receptor-binding paracrine growth factor with anti-inflammatory properties and indispensable roles in vascular development and stability. We used a stable variant of angiopoietin-1 (COMP-Ang1) to test whether ex vivo intracoronary treatment with a single dose of COMP-Ang1 in donor Dark Agouti rat heart subjected to 4-h cold ischemia would prevent microvascular dysfunction and inflammatory responses in the fully allogeneic recipient Wistar Furth rat. COMP-Ang1 reduced endothelial cell-cell junction disruption of the donor heart in transmission electron microscopy during 4-h cold ischemia, improved myocardial reflow, and reduced microvascular leakage and cardiomyocyte injury of transplanted allografts during IRI. Concurrently, the treatment reduced expression of danger signals, dendritic cell maturation markers, endothelial cell adhesion molecule VCAM-1 and RhoA/Rho-associated protein kinase activation and the influx of macrophages and neutrophils. Furthermore, COMP-Ang1 treatment provided sustained anti-inflammatory effects during acute rejection and prevented the development of cardiac fibrosis and allograft vasculopathy. These results suggest donor heart treatment with COMP-Ang1 having important clinical implications in the prevention of primary and subsequent long-term injury and dysfunction in cardiac allografts.
Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.|Cardiac Surgery, Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.
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Syrjälä
Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.|Cardiac Surgery, Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.
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Nykänen
Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.|Cardiac Surgery, Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.
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Tuuminen
Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.|Cardiac Surgery, Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.
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Raissadati
Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.|Cardiac Surgery, Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.
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Keränen
Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.|Cardiac Surgery, Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.
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Arnaudova
Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.|Cardiac Surgery, Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.
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Krebs
Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
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Koh
Wihuri Research Institute, Translational Cancer Biology Program and Helsinki University Central Hospital, Helsinki, Finland.
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Alitalo
Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.|Cardiac Surgery, Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.
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Lemström
D000818:Animals; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000517:prevention & control*; D014019:Tissue Donors
C515576:COMP-Ang1 fusion protein; D011993:Recombinant Fusion Proteins
Animal models: murine; innate immunity; ischemia reperfusion injury (IRI); rejection; vascular biology