Cystathionine γ-lyase, a H2S-generating enzyme, is a GPBAR1-regulated gene and contributes to vasodilation caused by secondary bile acids.
GPBAR1 is a bile acid-activated receptor (BAR) for secondary bile acids, lithocholic (LCA) and deoxycholic acid (DCA), expressed in the enterohepatic tissues and in the vasculature by endothelial and smooth muscle cells. Despite that bile acids cause vasodilation, it is unclear why these effects involve GPBAR1, and the vascular phenotype of GPBAR1 deficient mice remains poorly defined. Previous studies have suggested a role for nitric oxide (NO) in regulatory activity exerted by GPBAR1 in liver endothelial cells. Hydrogen sulfide (H2S) is a vasodilatory agent generated in endothelial cells by cystathionine-γ-lyase (CSE). Here we demonstrate that GPBAR1 null mice had increased levels of primary and secondary bile acids and impaired vasoconstriction to phenylephrine. In aortic ring preparations, vasodilation caused by chenodeoxycholic acid (CDCA), a weak GPBAR1 ligand and farnesoid-x-receptor agonist (FXR), was iberiotoxin-dependent and GPBAR1-independent. In contrast, vasodilation caused by LCA was GPBAR1 dependent and abrogated by propargyl-glycine, a CSE inhibitor, and by 5β-cholanic acid, a GPBAR1 antagonist, but not by N(5)-(1-iminoethyl)-l-ornithine (l-NIO), an endothelial NO synthase inhibitor, or iberiotoxin, a large-conductance calcium-activated potassium (BKCa) channels antagonist. In venular and aortic endothelial (HUVEC and HAEC) cells GPBAR1 activation increases CSE expression/activity and H2S production. Two cAMP response element binding protein (CREB) sites (CREs) were identified in the CSE promoter. In addition, TLCA stimulates CSE phosphorylation on serine residues. In conclusion we demonstrate that GPBAR1 mediates the vasodilatory activity of LCA and regulates the expression/activity of CSE. Vasodilation caused by CDCA involves BKCa channels. The GPBAR1/CSE pathway might contribute to endothelial dysfunction and hyperdynamic circulation in liver cirrhosis.
Department of Surgical and Biomedical Sciences, University of Perugia, Perugia, Italy;
Barbara
B
Renga
Department of Pharmacy, University of Naples "Federico II," Naples, Italy;
Mariarosaria
M
Bucci
Department of Surgical and Biomedical Sciences, University of Perugia, Perugia, Italy;
Sabrina
S
Cipriani
Department of Surgical and Biomedical Sciences, University of Perugia, Perugia, Italy;
Adriana
A
Carino
Department of Pharmacy, University of Salerno, Salerno, Italy; and.
Maria Chiara
MC
Monti
Department of Pharmacy, University of Naples "Federico II," Naples, Italy;
Angela
A
Zampella
Department of Pharmacy, University of Naples "Federico II," Naples, Italy;
Antonella
A
Gargiulo
Department of Pharmacy, University of Naples "Federico II," Naples, Italy;
Roberta
R
d'Emmanuele di Villa Bianca
Azienda Ospedaliera di Perugia, Perugia, Italy.
Eleonora
E
Distrutti
Department of Surgical and Biomedical Sciences, University of Perugia, Perugia, Italy; stefano.fiorucci@unipg.it.
Stefano
S
Fiorucci
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism* / Q000494:pharmacology; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D002793:Cholic Acids / Q000494:pharmacology; D003542:Cystathionine gamma-Lyase / Q000235:genetics* / Q000378:metabolism; D042783:Endothelial Cells; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008095:Lithocholic Acid / Q000494:pharmacology; D018345:Mice, Knockout; D009952:Ornithine / Q000031:analogs & derivatives / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics*
D001647:Bile Acids and Salts; D002793:Cholic Acids; C473772:GPBAR1 protein, human; C513561:Gpbar1 protein, mouse; D010455:Peptides; D043562:Receptors, G-Protein-Coupled; D002635:Chenodeoxycholic Acid; C065027:N(G)-iminoethylornithine; D008095:Lithocholic Acid; C064719:iberiotoxin; D009952:Ornithine; D003542:Cystathionine gamma-Lyase; C007036:cholanic acid; D006862:Hydrogen Sulfide
GPBAR1; bile acids; hydrogen sulfide; nitric oxide