Introduction and objectives Despite advances in the overall management of Pulmonary Arterial Hypertension (PAH) significant morbidity and poor prognosis remain a major clinical problem. Identifying key pathways in the pathogenesis of this disease will allow development of more targeted therapies aimed at treating PAH. There is emerging evidence to support that Tumour Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) plays an important role in vascular biology. We have recently reported expression of TRAIL from lesions of patients with advanced Idiopathic PAH. To further determine the role of TRAIL in the pathogenesis of PAH we used a diet-induced murine model of PAH.
Methods ApoE−/−, TRAIL−/− and ApoE−/−/TRAIL−/− double null mice were fed chow or Paigen (high fat, cholate-containing diet) for 8 weeks. They underwent echocardiographic assessment prior to right heart catheterisation using the internal jugular venous route. The heart and right lung were perfusion fixed with 10% formalin for subsequent determination of right ventricular mass and Immunohistochemistry of pulmonary vascular lesions. The left lung was immediately frozen in liquid nitrogen for subsequent determination of protein and RNA by western Immunoblotting and quantitative PCR. Identical to above ApoE−/−/TRAIL−/− double null mice were also treated with recombinant murine TRAIL, or saline (4 week infusion via an osmotic mini pump) at the time of commencing the diet for 8 weeks.
Results Compared to control chow fed mice, ApoE−/− mice fed the Paigen diet developed significant elevation of Right Ventricular Systolic Pressure (RVSP) (23 mm Hg vs 50 mm Hg n=7 p<0.001), pulmonary vascular resistance and arteriolar remodelling. ApoE−/−/TRAIL−/− double null mice fed the Paigen diet, were protected from these haemodynamic (RVSP 27 mm Hg n=6 p<0.05) and pulmonary vascular remodelling changes. Moreover, the PAH phenotype was re-established in the ApoE−/−/TRAIL−/− double null mice by the administration of exogenous recombinant TRAIL.
Conclusions TRAIL is a critical mediator in disease pathogenesis of PAH in the diet-induced murine model of PAH. Targeting TRAIL could provide a novel therapeutic approach to the treatment of PAH. Work is ongoing to determine if this approach can stabilise or reverse established disease, in both this, and rat, experimental models of PAH.
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