Small Molecule Tyrosine Kinase Inhibitor Nintedanib Reduces Development of Cardiac Allograft Vasculopathy in Murine Aortic Allografts

Gocht A, Spriewald B, Distler J, Ramsperger-Gleixner M, Ensminger SM, Weyand M, Heim C (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Book Volume: 4

Journal Issue: 7

DOI: 10.1097/TXD.0000000000000804

Abstract

Background: Nintedanib is a small molecule tyrosine kinase inhibitor that blocks the action of the platelet-derived growth factor receptor (PDGFR), the vascular endothelial growth factor receptor (VEGFR) and the fibroblast growth factor receptor. All of these receptors have been shown to be involved in the development of cardiac allograft vasculopathy (CAV) after heart transplantation. We therefore hypothesized that blocking these tyrosine kinase receptors with nintedanib could prevent CAV. Methods: CBA/JRj (H2k) mice underwent an abdominal aortic transplantation with a graft derived from fully allogeneic C57BL/6JRj (H2b) mice. Nintedanib was given daily from the first day after transplantation until harvest on day 14 for polymerase chain reaction analysis of intragraft cytokine expression or harvest on day 30 for histological analysis of the graft. Results: Nintedanib treatment resulted in significantly reduced neointima formation in the aortic graft compared with untreated control allografts. Interestingly, the immigration of smooth muscle cells into the neointima was markedly reduced while graft infiltrating macrophages and T cells were not altered in nintedanib-treated animals. The expression of the growth factor PDGF was significantly reduced in the nintedanib group going along with a distinctly reduced expression of the corresponding receptors PDGFR α and -β. Conclusions: Treatment with nintedanib caused a significant reduction of CAV development after aortic transplantation in mice. We hypothesize the attenuated neointima formation in nintedanib-treated animals to be mediated by a direct inhibition of intimal smooth muscle cell proliferation via reduced expression of PDGF and the appropriate receptors PDGFR α + β.

Authors with CRIS profile

Involved external institutions

Herz- und Diabeteszentrum Nordrhein-Westfalen Germany (DE)

How to cite

APA:

Gocht, A., Spriewald, B., Distler, J., Ramsperger-Gleixner, M., Ensminger, S.M., Weyand, M., & Heim, C. (2018). Small Molecule Tyrosine Kinase Inhibitor Nintedanib Reduces Development of Cardiac Allograft Vasculopathy in Murine Aortic Allografts. Transplantation Direct, 4(7). https://doi.org/10.1097/TXD.0000000000000804

MLA:

Gocht, Annika, et al. "Small Molecule Tyrosine Kinase Inhibitor Nintedanib Reduces Development of Cardiac Allograft Vasculopathy in Murine Aortic Allografts." Transplantation Direct 4.7 (2018).

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