Evaluation of a combination therapy using riociguat and a TAK-1 inhibitor in the Sugen 5416/hypoxia rat model of pulmonary arterial hypertension

[Speaker] Laura Moreno:1,2,3
[Co-author] Daniel Morales-Cano:1,2,3, Jose Luis Izquierdo:2,4, Bianca Barreira:1,2,3, Sergio Esquivel-Ruiz:1,2,3, Maria Callejo:1,2,3, Gema Mondejar-Parreno:1,2,3, Angel Cogolludo:1,2,3, Jesus Ruiz-Cabello:2,5, Francisco Perez-Vizcaino:1,2,3
1:Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid (UCM), Spain, 2:Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain, 3:Gregorio Maranon Biomedical Research Institution (IiSGM), Madrid, Spain, 4:National Center for Cardiovascular Research (CNIC), Madrid, Spain, 5:School of Pharamacy, Universidad Complutense de Madrid (UCM), Spain

Background: Despite increasing evidences suggest that pulmonary arterial hypertension (PAH) is a complex disease involving vasoconstriction, thrombosis, inflammation, metabolic dysregulation and vascular proliferation, all the drugs approved for PAH mainly act as vasodilating agents. Since excessive TGF-B signalling is believed to be a critical factor in pulmonary vascular remodelling, we hypothesized that blocking TGFB-activated kinase 1 (TAK-1), alone or in combination with a vasodilator therapy (i.e., riociguat) could achieve a greater therapeutic benefit.

Methods: PAH was induced in male Wistar rats by a single injection of the VEGF receptor antagonist SU5416 (20mg/Kg) followed by exposure to hypoxia (10 percent O2) for 21 days. Two weeks after SU5416 administration, vehicle, riociguat (3mg/kg/day), the TAK-1 inhibitor (5z)-7-oxozeaenol (OXO, 3mg/kg/day) or both drugs combined were administered for 7 days. Metabolic profiling of right ventricle (RV) tissue was performed by magnetic resonance spectroscopy and the differences between groups were analysed by Principal Component Analysis.

Results: In vitro, riociguat induced potent vasodilator effects in isolated pulmonary arteries (PA) with negligible antiproliferative effects in PA smooth muscle cells (PASMCs). In contrast, OXO effectively inhibited proliferation of PASMCs but had no acute vasodilator effects.
In vivo, treatment with riociguat partially reduced the increase in pulmonary arterial pressure (PAP), RV hypertrophy (RVH) and pulmonary vascular remodelling, attenuated the dysregulation of inosine, glucose, creatine and phosphocholine (PC) in RV and fully abolished the increase in lung IL-1B expression. By contrast, OXO significantly reduced pulmonary vascular remodelling and attenuated the metabolic shifts of glucose and PC in RV but had no effects on PAP or RVH. Importantly, combined therapy had an additive effect on pulmonary vascular remodelling and induced an additional normalization of cardiac glutamine levels but it did not improve the effects induced by riociguat alone on pulmonary pressure or right ventricle remodelling. None of the treatments were able to attenuate pulmonary endothelial dysfunction and hyperresponsiveness to serotonin in isolated PA.

Conclusions: Our results suggest that inhibition of TAK-1 induces antiproliferative effects and its addition to short-term vasodilator therapy enhance the beneficial effects on pulmonary vascular remodelling but does not allow to reverse experimental PAH.

Supported by CP12_03304, PI15_01100.

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