Inhibition of the wnt Pathway as an Option for Preventing Cardiac Allograft Vasculopathy

Objectives: The complex wnt pathway is important for tissue homeostasis in the adult. Its dysregulation is also known to be associated with a plethora of diseases—among others diseases of the cardiovascular system. Chronic rejection in the form of cardiac allograft vasculopathy (CAV) after heart transplantation, a major obstacle for transplanted patients, is characterized by the development of a SMC-rich neointima. Several reports describe an inhibition of smooth muscle cell (SMC) proliferation after blocking the wnt pathway which implies a potential benefit of wnt inhibitors in preventing CAV.

Methods: Human (hu) und murine (mu) SMCs were treated with different dosages of the two wnt inhibitors XAV-939 and ICG-001. Proliferation of the SMCs was determined by analyzing cell presto blue metabolism. XAV-939 was additionally used to treat mice after allogeneic aortic transplantation (5mg/kg XAV-939 once per day). Aortic grafts were histologically measured for neointima development 30 days after the transplantation. Additionally, immuno histologic expression of β-catenin, the central player of the wnt pathway, was analyzed.

Results: XAV-939 and ICG-001 both caused a dose-dependent and reproducible inhibition of huSMC and muSMC proliferation in vitro. This effect was obviously stronger in ICG-001 treated cells. However, treatment with 5 mg/kg/d XAV-939 did not prevent neointima formation in mice after allogeneic aortic transplantation (52.3 ± 10.0% luminal occlusion in untreated grafts vs. 54.9 ± 11.5% in XAV-939 treated grafts; p = 1.00). There could not be detected any relevant differences in the expression on β-Catenin in the neointima of allografts with or without XAV-939 treatment (13.9 ± 10.8% for untreated allografts vs. 18.6 ± 6.0%; p = 0.55).

Conclusion: Inhibition of the wnt pathway with two different inhibitors had antiproliferative effects on cultivated huSMCs and muSMCs. SMC proliferation is one of the main pathomechanisms for the development of a neointima as the characteristic feature of CAV after transplantation. Nevertheless, XAV-939 could not reduce neointima formation in a mouse model of allogeneic aortic transplantation. In vivo experiments with ICG-001, which showed the stronger effect in vitro, are currently ongoing.