title: Reversal of Endothelial Dysfunction by GPBAR1 Agonism in Portal Hypertension Involves a AKT/FOXOA1 Dependent Regulation of H2S Generation and Endothelin-1.
abstract: BACKGROUND
  GPBAR1 is a bile acids activated receptor expressed in entero-hepatic tissues. In the liver expression of GPBAR1 is restricted to sinusoidal and Kuppfer cells. In the systemic circulation vasodilation caused by GPBAR1 agonists is abrogated by inhibition of cystathione-γ-liase (CSE), an enzyme essential to the generation of hydrogen sulfide (H2S), a vasodilatory agent. Portal BAR501 is a semisynthetic bile acid derivative endowed with a potent and selective agonistic activity toward GPBAR1.
  
  
  METHODS
  Cirrhosis was induced in mice by carbon tetrachloride (CCL4) administration for 9 weeks. Liver endothelial dysfunction was induced by feeding wild type and Gpbar1-/- mice with methionine for 4 weeks. In both models, mice were administered BAR501, 15 mg/kg/day.
  
  
  RESULTS
  By transactivation assay we demonstrate that BAR501 is a selective GPBAR1 agonist devoid of any FXR agonistic activity. In naïve rats, BAR501 effectively reduced hepatic perfusion pressure and counteracted the vasoconstriction activity of norepinephrine. In the CCl4 model, 9 weeks treatment with BAR501 effectively protected against development of endothelial dysfunction by increasing liver CSE expression and activity and by reducing endothelin (ET)-1 gene expression. In mice feed methionine, treatment with BAR501 attenuated endothelial dysfunction and caused a GPBAR1-dependent regulation of CSE. Using human liver sinusoidal cells, we found that modulation of CSE expression/activity is mediated by both genomic (recruitment of CREB to CRE in the CSE promoter) and non-genomic effects, involving a Akt-dependent phosporylation of CSE and endothelial nitric oxide (NO) synthase (eNOS). BAR501, phosphorylates FOXO1 and inhibits ET-1 transcription in liver sinusoidal cells.
  
  
  CONCLUSIONS
  BAR501, a UDCA-like GPBAR1 agonist, rescues from endothelial dysfunction in rodent models of portal hypertension by exerting genomic and non-genomic effects on CSE, eNOS and ET-1 in liver sinusoidal cells.
authors.affiliation: Department of Surgical and Biomedical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.affiliation: Department of Medicine, University of Perugia, Perugia, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cipriani
authors.affiliation: Department of Surgical and Biomedical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Carino
authors.affiliation: Department of Surgical and Biomedical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Simonetti
authors.affiliation: Department of Pharmacy, University of Naples 'Federico II', Naples, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
authors.affiliation: Department of Surgical and Biomedical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002777:Cholestanols / Q000494:pharmacology; D019332:Endothelin-1 / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D006975:Hypertension, Portal / Q000188:drug therapy / Q000503:physiopathology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051058:Oncogene Protein v-akt / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives
chemical_list: C000608430:6-ethyl-3,7-dihydroxycholan-24-ol; D001647:Bile Acids and Salts; D002777:Cholestanols; D019332:Endothelin-1; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C513561:Gpbar1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D014580:Ursodeoxycholic Acid; D051058:Oncogene Protein v-akt; D006862:Hydrogen Sulfide