Dataset Information

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-?-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.

SUBMITTER: Renga B

PROVIDER: S-EPMC4634759 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Publications

Reversal of Endothelial Dysfunction by GPBAR1 Agonism in Portal Hypertension Involves a AKT/FOXOA1 Dependent Regulation of H2S Generation and Endothelin-1.

Renga Barbara B Cipriani Sabrina S Carino Adriana A Simonetti Michele M Zampella Angela A Fiorucci Stefano S

PloS one 20151105 11

<h4>Background</h4>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 t ...[more]

PMID: 26539823

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Project description:BackgroundAlthough several risk factors for erectile dysfunction may be present in patients with cirrhosis, data on the actual prevalence and cause of erectile dysfunction is limited. The International Index of Erectile Function-5 (IIEF-5) is a well-validated survey to determine the presence and severity of erectile dysfunction in men. We assessed (i) the prevalence and severity of erectile dysfunction, and (ii) risk factors for erectile dysfunction in patients with cirrhosis.MethodsIn this prospective study, erectile dysfunction was defined as: absent (>21 IIEF-5-points), mild (12-21) and severe (5-11). Patients with overt hepatic encephalopathy, active alcohol abuse, extrahepatic malignancy, previous urologic surgery, previous liver transplantation and severe cardiac conditions were excluded.ResultsAmong n = 151 screened patients, n = 41 met exclusion criteria and n = 30 were sexually inactive. Thus, a final number of n = 80 male patients with cirrhosis were included. Patient characteristics: age: 53 ± 9 years; model for end-stage liver disease score (MELD): 12.7 ± 3.9; Child-Pugh score (CPS) A: 30 (37.5%), B: 35 (43.8%), C: 15 (18.7%); alcohol: 38 (47.5%), viral: 25 (31.3%), alcohol/viral: 7 (8.8%) and others: 10 (12.5%). The presence of erectile dysfunction was found in 51 (63.8%) patients with 44 (55%) and 7 (8.8%) suffering from mild-to-moderate and moderate-to-severe erectile dysfunction. Mean MELD and hepatic venous pressure gradient (HVPG) were significantly higher in patients with erectile dysfunction (P = .021; P = .028). Child-Pugh score C, MELD, creatinine, age, arterial hypertension, diabetes, low libido, low testosterone and high HVPG were associated with the presence of erectile dysfunction. Interestingly, beta-blocker therapy was not associated with an increased risk. In multivariate models, arterial hypertension (OR: 6.36 [1.16-34.85]; P = .033), diabetes (OR: 7.40 [1.31-41.75]; P = .023), MELD (OR: 1.19 [1.03-1.36]; P = .015) and increasing HVPG (n = 48; OR: 1.11 [1.002-1.23]; P = .045) were independent risk factors for the presence of erectile dysfunction.ConclusionAbout two-thirds of male patients with cirrhosis show erectile dysfunction. Severity of liver dysfunction, portal hypertension, arterial hypertension and diabetes were identified as risk factors for erectile dysfunction.

Dataset Information

Reversal of Endothelial Dysfunction by GPBAR1 Agonism in Portal Hypertension Involves a AKT/FOXOA1 Dependent Regulation of H2S Generation and Endothelin-1.

Background

Methods

Results

Conclusions

Publications

Reversal of Endothelial Dysfunction by GPBAR1 Agonism in Portal Hypertension Involves a AKT/FOXOA1 Dependent Regulation of H2S Generation and Endothelin-1.

Similar Datasets

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