Cardiopulmonary protective effects of the selective FXR agonist obeticholic acid in the rat model of monocrotaline-induced pulmonary hypertension. Issue 165 (January 2017)

• Record Type: Journal Article
• Authors: Vignozzi, Linda; Morelli, Annamaria; Cellai, Ilaria; Filippi, Sandra; Comeglio, Paolo; Sarchielli, Erica; Maneschi, Elena; Vannelli, Gabriella Barbara; Adorini, Luciano; Maggi, Mario
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 165:Part B(2017)
• Page Start: 277
• Page End: 292
• Publication Date: 2017-01
• Subjects: ACE2 angiotensin-converting enzyme 2 -- Ach acetylcholine -- BA bile acid -- BMP2 bone morphogenetic protein 2 -- BMPR1A bone morphogenetic protein receptor 1-a -- BW body weight -- CDCA chenodeoxycholic acid -- cGMP cyclic guanosine monophosphate -- COX2 cyclooxygenase-2 -- ECs endothelial cells -- ET-1 endothelin-1 -- ETA endothelin receptor type A -- ETB endothelin receptor type B -- FXR farnesoid X receptor -- GCSa3 guanylate cyclase subunit type 1a3 -- GCSb3 guanylate cyclase subunit type 1b3 -- IL-1β interleukin 1β -- IL-6 interleukin 6 -- LV left ventricle -- MCP-1 monocyte chemoattractant protein-1 -- MCT monocrotaline -- MMP2 matrix metalloproteinase-2 -- MMP9 matrix metalloproteinase-9 -- NF-kB nuclear factor kB -- NO nitric oxide -- eNOS endothelial nitric oxide synthase -- OCA obeticholic acid -- PAH pulmonary arterial hypertension -- PDE5 phosphodiesterase type 5 -- PKG1 cGMP-dependent protein kinase 1 -- RhoA ras homolog gene family member A -- ROCK1 Rho-associated protein kinase 1 -- ROCK2 Rho-associated protein kinase 2 -- RV right ventricle -- RVH right ventricular hypertrophy -- S interventricular septum -- sCG soluble guanylate cyclase -- SD Sprague-Dawley -- SHP small heterodimer partner -- αSMA alpha-smooth muscle actin -- SM22 transgelin -- SNP sodium nitroprusside -- TAD tadalafil -- TGFβ1 transforming growth factor beta 1 -- TIMP1 tissue inhibitor of metalloproteinases 1 -- TIMP2 tissue inhibitor of metalloproteinases 2 -- TNFα tumor necrosis factor alpha -- TTF-1 thyroid transcription factor-1 -- VEGF vascular endothelial growth factor -- WT wall thickness; Monocrotaline -- Pulmonary hypertension -- Inflammation -- Farnesoid X receptor -- Obeticholic acid; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2016.07.004
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: FXR activation is able to suppress the inflammatory response after lung injury. OCA treatment attenuated the MCT-induced pathogenic inflammatory mechanisms. OCA treatment induced profound beneficial effects on lung histology. MCT significantly reduced the treadmill endurance, which is normalized by OCA. OCA can restore the balance between relaxant and contractile pathways in the lung. 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 30 mg/kg, daily for 5 days 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 (30 mg/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.