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

Abstract

BackgroundNintedanib 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.MethodsCBA/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.ResultsNintedanib 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.ConclusionsTreatment 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.

Direct Impact of Human Platelets on the Development of Transplant Arteriosclerosis

“…40-43 Blocking the PDGFRβ results in hampered SMC migration. 44 Other potential mechanisms include CD40L on activated platelets inducing endothelial cells to secrete signature chemokines and to express adhesion molecules, such as ICAM-1 and VCAM-1, 45 and have been investigated in previous experimental mouse studies. 10,11…”

“…[40][41][42][43] Blocking the PDGFRβ results in hampered SMC migration. 44 Other potential mechanisms include CD40L on activated platelets inducing endothelial cells to secrete signature chemokines and to express adhesion molecules, such as ICAM-1 and VCAM-1, 45 and have been investigated in previous experimental mouse studies. 10,11 In summary, our findings affirm both in vitro-and in vivo-activated hPlts as an isolated factor responsible for the development of transplant arteriosclerosis in a humanized mouse artery xenograft model and support the therapeutic usage of the antiplatelet agents such as clopidogrel for effectively reducing transplant arteriosclerosis in experimental vascular grafts.…”