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Effects of the FGF receptor-1 inhibitor, infigratinib, with or without sildenafil, in experimental pulmonary arterial hypertension.

ABSTRACT: BACKGROUND AND PURPOSE:Pulmonary arterial hypertension (PAH) is a progressive disease associated with high morbidity and mortality, despite advances in medical therapy. We compared the effects of infigratinib (NVP-BGJ398), a new FGF receptor-1 inhibitor, with or without the PDE-5 inhibitor sildenafil, on vascular function and remodelling as well as on gene expression of signal transducers for receptors of TGF-? (Smads-1/2/4) and transcription factor of endothelial-mesenchymal transition (Twist-1) in established experimental PAH. Types I and III pro-collagen and TGF-? expressions in lung fibroblasts were analysed in vitro after the different treatments. EXPERIMENTAL APPROACH:PAH was induced in male Wistar rats with monocrotaline. 14 days later, treatments [sildenafil (SIL), infigratinib (INF) or their combination (SIL+INF)] were given for another 14 days. On Day 28, echocardiography and haemodynamic assays were performed, and lungs and pulmonary vessels were removed for analysis by histology, immunohistochemistry and RT-PCR. Fibroblasts prepared from PAH lungs were also analysed for TGF-? and pro-collagen. KEY RESULTS:Only the combination of infigratinib and sildenafil significantly improved right ventricular systolic pressure and vascular remodelling parameters (right ventricular hypertrophy, smooth muscle ?-actin, vessel wall thickness, and vascular collagen content). Infigratinib may act by reducing gene expression of Smads-1/4 and Twist-1 in lung tissue, as well as TGF-? and types I and III pro-collagen in lung fibroblasts. CONCLUSIONS AND IMPLICATIONS:In this model of monocrotaline-induced PAH, the combination of the new inhibitor of FGF receptor-1, infigratinib, and sildenafil effectively improved haemodynamics and decreased vascular remodelling.

SUBMITTER: Felix NS

PROVIDER: S-EPMC6932937 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Effects of the FGF receptor-1 inhibitor, infigratinib, with or without sildenafil, in experimental pulmonary arterial hypertension.

Felix Nathane Santanna NS de Mendonça Lucas L Braga Cassia Lisboa CL da Silva Jaqueline Soares JS Samary Cynthia Dos Santos CDS Vieira Juliana Borges JB Cruz Fernanda F Rocha Nazareth de Novaes NN Zapata-Sudo Gisele G Rocco Patricia Rieken Macedo PRM Silva Pedro Leme PL

British journal of pharmacology 20191205 23

<h4>Background and purpose</h4>Pulmonary arterial hypertension (PAH) is a progressive disease associated with high morbidity and mortality, despite advances in medical therapy. We compared the effects of infigratinib (NVP-BGJ398), a new FGF receptor-1 inhibitor, with or without the PDE-5 inhibitor sildenafil, on vascular function and remodelling as well as on gene expression of signal transducers for receptors of TGF-β (Smads-1/2/4) and transcription factor of endothelial-mesenchymal transition ...[more]

PMID: 31351013

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Dataset Information

Effects of the FGF receptor-1 inhibitor, infigratinib, with or without sildenafil, in experimental pulmonary arterial hypertension.

Publications

Effects of the FGF receptor-1 inhibitor, infigratinib, with or without sildenafil, in experimental pulmonary arterial hypertension.

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