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Published on: February 14, 2022
Donor Heart Treatment With COMP-Ang1 Limits Ischemia-Reperfusion Injury and Rejection of Cardiac Allografts
S O Syrjälä1,2, A I Nykänen1,2, R Tuuminen1,2
1Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
Insights
Treatment with COMP-angiopoietin-1 (COMP-Ang1) protects donor hearts from ischemia-reperfusion injury (IRI) and inflammation. This approach may prevent primary graft dysfunction and long-term complications after heart transplantation.
Area of Science:
- Cardiovascular Research
- Transplantation Immunology
- Regenerative Medicine
Background:
- Primary graft dysfunction, caused by ischemia-reperfusion injury (IRI), is a leading cause of death post-heart transplantation.
- Angiopoietin-1 (Ang-1) is a growth factor with critical roles in vascular stability and anti-inflammatory functions.
- A stable variant, COMP-Ang1, was investigated for its protective effects in cardiac allografts.
Purpose of the Study:
- To evaluate the efficacy of ex vivo COMP-Ang1 treatment in preventing microvascular dysfunction and inflammation in donor rat hearts subjected to cold ischemia.
- To assess the impact of COMP-Ang1 on IRI-induced damage, inflammatory cell infiltration, and long-term allograft outcomes.
Main Methods:
- Donor Dark Agouti rat hearts underwent 4-hour cold ischemia followed by transplantation into allogeneic Wistar Furth rats.
- Hearts were treated ex vivo with a single dose of COMP-Ang1.
- Microvascular integrity, inflammatory markers, cell infiltration, and long-term complications like fibrosis and vasculopathy were analyzed.
Main Results:
- COMP-Ang1 treatment preserved endothelial cell-cell junctions during ischemia.
- It improved myocardial reflow, reduced microvascular leakage, and protected cardiomyocytes from IRI.
- COMP-Ang1 suppressed inflammatory signals, dendritic cell maturation, VCAM-1 expression, and immune cell influx.
- Sustained anti-inflammatory effects were observed, preventing cardiac fibrosis and allograft vasculopathy.
Conclusions:
- Ex vivo COMP-Ang1 treatment of donor hearts effectively mitigates IRI and acute rejection.
- This therapeutic strategy holds significant potential for preventing both primary graft dysfunction and long-term complications in cardiac allografts.
- COMP-Ang1 represents a promising therapeutic agent for improving heart transplant outcomes.
Abstract:
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.
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