Innovative Approaches (Videos Available)

Thursday July 05, 2018 from 09:45 to 11:00

Room: N-117/118

626.2 Blockade of tyrosine kinases as preventive strategy against cardiac allograft vasculopathy in a murine aortic transplant model (Video Available)

Award Winner

Christian Heim, Germany has been granted the TTS Young Investigator Scientific Award

Christian Heim, Germany

Cardiac Surgeon
Cardiac Surgery
University of Erlangen

Abstract

Blockade of Tyrosine Kinases as Preventive Strategy Against Cardiac Allograft Vasculopathy in a Murine Aortic Transplant Model

Annika Gocht1, Jörg Distler2, Bernd Spriewald2, Martina Ramsperger-Gleixner1, Stephan M Ensminger3, Michael Weyand1, Christian Heim1.

1Cardiac Surgery, University of Erlangen, Erlangen, Germany; 2Medicine, University of Erlangen, Erlangen, Germany; 3Cardiac Surgery, HDZ NRW, Bad Oeynhausen, Germany

Objectives: Previous reports suggest a role of platelet derived growth factor (PDGF) in the development of cardiac allograft vasculopathy (CAV). The pharmaceutical blockade of tyrosine kinases may alter the expression of different growth factor receptors: platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) and hereby play a role in the context of cardiac allograft vasculopathy. Therefore the aim of this study was to determine the impact of tyrosine kinase inhibition on the development of cardiac allograft vasculopathy in a mouse model.
Methods: Fully allogeneic mouse aortas from C57BL/6 mice (H2b) were abdominally transplanted into CBA mice (H2k). Recipients were treated with tyrosine kinase inhibitor nintedanib (60mg/kg/d) and sacrificed on day 14 for cytokine PCR analysis of the graft or on day 30 for (immuno-) histological measurements.
Results: Aortic grafts treated with tyrosine kinase inhibitor nintedanib showed significantly reduced neointima proliferation (33% ± 12% vs. 54% ± 13%) after 30 days. These findings go along with significantly reduced amounts of smooth muscle cells (SMC) (20% ± 9% vs. 42% ± 10%) within the neointima. Further immunofluorescence analysis revealed no relevant difference in the percentages of dendritic cells, macrophages and CD4+ T-cells within the neointima. Meanwhile, the expression of both PDGF receptor subtypes α and β was reduced within the neointima of the aortic grafts. Additionally, we found a reduced gene expression of the ligand PDGF-B, a mitogen for SMC, and of the pro-inflammatory CD40L.
Conclusion: PDGF receptor blockade via inhibition of receptor tyrosine kinases seems to be a promising way to prevent the development of cardiac allograft vasculopathy in a mouse model. We would speculate a direct inhibition of the migration and proliferation of smooth muscle cells with a resulting decrease of neointima formation as the mechanism of action.



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