Reversal of Endothelial Dysfunction by GPBAR1 Agonism in Portal Hypertension Involves a AKT/FOXOA1 Dependent Regulation of H2S Generation and Endothelin-1.
Reversal of Endothelial Dysfunction by GPBAR1 Agonism in Portal Hypertension Involves a AKT/FOXOA1 Dependent Regulation of H2S Generation and Endothelin-1.
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DOI：
10.1371/journal.pone.0141082
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Fiorucci S
中科院分区：
文献类型：
--
作者：
Renga B;Cipriani S;Carino A;Simonetti M;Zampella A;Fiorucci S
GPBAR1是一种胆汁酸激活受体，表达于肝肠道组织。在肝脏中，GPBAR1的表达仅限于肝窦和Kuppfer细胞。在体循环中，GPBAR1激动剂引起的血管扩张可通过抑制胱硫酮γ-liase(CSE)来消除，CSE是血管扩张剂硫化氢(H2S)产生所必需的一种酶。门脉BAR501是一种半合成的胆汁酸衍生物，对GPBAR1具有强烈的选择性激动剂活性。用四氯化碳(CCl4)诱导小鼠9周肝硬变。用蛋氨酸喂养野生型和Gpbar1-/-小鼠4周，诱导肝内皮细胞功能障碍。在两种模型中，小鼠均给予BAR501，15 mg/kg/d。通过转录激活实验，我们证明BAR501是一种选择性的GPBAR1激动剂，不具有任何FXR激动剂活性。在幼稚大鼠中，BAR501有效降低肝脏灌流压，并拮抗去甲肾上腺素的血管收缩作用。在CCl4模型中，BAR501治疗9周通过增加肝脏CSE的表达和活性，并通过降低内皮素(ET)-1的基因表达，有效地预防内皮功能障碍的发展。在饲喂蛋氨酸的小鼠中，BAR501治疗减轻了内皮功能障碍，并导致了GPBAR1依赖的CSE调节。利用人肝窦细胞，我们发现CSE表达/活性的调节既受基因组(CSE启动子中CREB对CRE的募集)和非基因组效应的调节，涉及Akt依赖的CSE磷酸化和内皮型一氧化氮合酶(ENOS)。BAR501，磷酸化FOXO1，抑制肝窦细胞ET-1转录。BAR501是一种UDCA样GPBAR1激动剂，通过对肝窦细胞中CSE、eNOS和ET-1的基因组和非基因组效应，拯救门脉高压啮齿动物模型中的内皮功能障碍。
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. 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. 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. 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.