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Therapeutic effects of the selective farnesoid X receptor agonist obeticholic acid in a monocrotaline-induced pulmonary hypertension rat model

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Abstract

Background

Activation of the farnesoid X receptor (FXR), a member of the nuclear receptor steroid superfamily, leads to anti-inflammatory and anti-fibrotic effects in several tissues, including the lung. We have recently demonstrated a protective effect of the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) in rat models of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and bleomycin-induced pulmonary fibrosis. The aim of the present study was to investigate whether the positive effects of OCA treatment could be exerted also in established MCT-induced PAH, i.e., starting treatment 2 weeks after MCT administration.

Methods

Rats with MCT-induced PAH were treated, 2 weeks after MCT administration, with OCA or tadalafil for two additional weeks. Pulmonary functional tests were performed at week 2 (before treatment) and four (end of treatment). At the same time points, lung morphological features and expression profile of genes related to smooth muscle relaxation/contraction and tissue remodeling were also assessed.

Results

2 weeks after MCT-induced injury, the treadmill resistance (a functional parameter related to pulmonary hypertension) was significantly decreased. At the same time point, we observed right ventricular hypertrophy and vascular remodeling, with upregulation of genes related to inflammation. At week 4, we observed a further worsening of the functional and morphological parameters, accompanied by dysregulation of inflammatory and extracellular matrix markers mRNA expression. Administration of OCA (3 or 10 mg/kg/day), starting 2 weeks after MCT-induced injury, significantly improved pulmonary function, effectively normalizing the exercise capacity. OCA also reverted most of the lung alterations, with a significant reduction of lung vascular wall thickness, right ventricular hypertrophy, and restoration of the local balance between relaxant and contractile pathways. Markers of remodeling pathways were also normalized by OCA treatment. Notably, results with OCA treatment were similar, or even superior, to those obtained with tadalafil, a recently approved treatment for pulmonary hypertension.

Conclusions

The results of this study demonstrate a significant therapeutic effect of OCA in established MCT-induced PAH, improving exercise capacity associated with reduction of right ventricular hypertrophy and lung vascular remodeling. Thus, OCA dosing in a therapeutic protocol restores the balance between relaxant and contractile pathways in the lung, promoting cardiopulmonary protective actions in MCT-induced PAH.

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Acknowledgements

This study has been supported by a scientific Grant from Intercept Pharmaceuticals (New York, NY).

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Authors and Affiliations

  1. Sexual Medicine and Andrology Unit, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, AOU Careggi, Viale Pieraccini, 6, 50139, Florence, Italy

    P. Comeglio, I. Cellai, C. Corno, M. Maggi & L. Vignozzi

  2. Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Department of NEUROFARBA, University of Florence, Florence, Italy

    S. Filippi

  3. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

    E. Sarchielli, A. Morelli & G. B. Vannelli

  4. Intercept Pharmaceuticals, New York, NY, USA

    L. Adorini

  5. I.N.B.B. (Istituto Nazionale Biostrutture E Biosistemi), Rome, Italy

    M. Maggi & L. Vignozzi

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  1. P. Comeglio
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  2. S. Filippi
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  3. E. Sarchielli
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  4. A. Morelli
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  5. I. Cellai
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  6. C. Corno
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  7. L. Adorini
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  8. G. B. Vannelli
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  9. M. Maggi
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  10. L. Vignozzi
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Corresponding author

Correspondence to L. Vignozzi.

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Conflict of interest

PC, SF, ES, AM, IC, CC, GBV, MM and LV have no conflicts of interest. LA is a scientific consultant for Intercept Pharmaceuticals.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Comeglio, P., Filippi, S., Sarchielli, E. et al. Therapeutic effects of the selective farnesoid X receptor agonist obeticholic acid in a monocrotaline-induced pulmonary hypertension rat model. J Endocrinol Invest 42, 951–965 (2019). https://doi.org/10.1007/s40618-019-1009-2

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