title: Cardiopulmonary protective effects of the selective FXR agonist obeticholic acid in the rat model of monocrotaline-induced pulmonary hypertension.
abstract: Farnesoid X receptor (FXR) activation by obeticholic acid (OCA) has been demonstrated to inhibit inflammation and fibrosis development and even induce fibrosis regression in liver, kidney and intestine in multiple disease models. OCA also inhibits liver fibrosis in nonalcoholic steatohepatitis patients. FXR activation has also been demonstrated to suppress the inflammatory response and to promote lung repair after lung injury. This study investigated the effects of OCA treatment (3, 10 or 30mg/kg, daily for 5days a week, for 7 and/or 28 days) on inflammation, tissue remodeling and fibrosis in the monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) rat model. Treatment with OCA attenuated MCT-induced increased pulmonary arterial wall thickness and right ventricular hypertrophy, by i) blunting pathogenic inflammatory mechanisms (downregulation of interleukin 6, IL-6, and monocyte chemoattractant protein-1, MCP-1) and ii) enhancing protective mechanisms counteracting fibrosis and endothelial/mesenchymal transition. MCT-injected rats also showed a marked decrease of pulmonary artery responsiveness to both endothelium-dependent and independent relaxant stimuli, such as acetylcholine and a nitric oxide donor, sodium nitroprusside. Administration of OCA (30mg/kg) normalized this decreased responsiveness. Accordingly, OCA treatment induced profound beneficial effects on lung histology. In particular, both OCA doses markedly reduced the MCT-induced medial wall thickness increase in small pulmonary arteries. To evaluate the objective functional improvement by OCA treatment of MCT-induced PAH, we performed a treadmill test and measured duration of exercise. MCT significantly reduced, and OCA normalized treadmill endurance. Results with OCA were similar, or even superior, to those obtained with tadalafil, a well-established treatment of PAH. In conclusion, OCA treatment demonstrates cardiopulmonary protective effects, modulating lung vascular remodeling, reducing right ventricular hypertrophy and significantly improving exercise capacity. Thus, OCA can restore the balance between relaxant and contractile pathways in the lung, promoting cardiopulmonary protective actions.
authors.affiliation: Sexual Medicine and Andrology Unit, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Vignozzi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Morelli
authors.affiliation: Sexual Medicine and Andrology Unit, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Cellai
authors.affiliation: Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Department of Neuroscience, Drug Research and Child Care, University of Florence, Florence, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Filippi
authors.affiliation: Sexual Medicine and Andrology Unit, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Comeglio
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Sarchielli
authors.affiliation: Sexual Medicine and Andrology Unit, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Maneschi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Gabriella Barbara
authors.initials: GB
authors.lastname: Vannelli
authors.affiliation: Intercept Pharmaceuticals, New York, NY, USA.
authors.forename: Luciano
authors.initials: L
authors.lastname: Adorini
authors.affiliation: Sexual Medicine and Andrology Unit, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy; I.N.B.B. (Istituto Nazionale Biostrutture e Biosistemi), Rome, Italy. Electronic address: mario.maggi@unifi.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Maggi
mesh_terms: D000818:Animals; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D005080:Exercise Test; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy*; D017380:Hypertrophy, Right Ventricular; D007249:Inflammation; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D055370:Lung Injury / Q000473:pathology; D008297:Male; D016686:Monocrotaline; D009929:Organ Size; D011651:Pulmonary Artery / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002635:Chenodeoxycholic Acid; D016686:Monocrotaline; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C464660:obeticholic acid
keywords: Farnesoid X receptor; Inflammation; Monocrotaline; Obeticholic acid; Pulmonary hypertension