Angiotensin II Activates IκB Kinase Phosphorylation of RelA at Ser536 to Promote Myofibroblast Survival and Liver Fibrosis
Angiotensin II Activates IκB Kinase Phosphorylation of RelA at Ser536 to Promote Myofibroblast Survival and Liver Fibrosis
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DOI：
10.1053/j.gastro.2009.02.081
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发表时间：
2009-06-01
期刊：
影响因子：
29.4
通讯作者：
Mann, Derek A.
中科院分区：
文献类型：
--
作者：
Oakley, Fiona;Teoh, Victoria;Mann, Derek A.
背景与目的：转录因子核因子 - κB（NF - κB）通过尚不明确的机制促进肝肌成纤维细胞的存活和纤维化形成。我们研究了血管紧张素II和IκB激酶（IKK）在调节NF - κB活性中的作用，以及这些蛋白质在啮齿动物和人类肝脏纤维化中的作用。
方法：通过免疫印迹和免疫组化分析检测NF - κB亚基RelA在丝氨酸536位点的磷酸化（P - Ser(536) - RelA）。使用表达RelA突变形式的载体、细胞可渗透的阻断肽以及RelA核转运和凋亡检测来评估P - Ser(536) - RelA的功能。将P - Ser(536) - RelA水平与慢性损伤大鼠肝脏切片以及接受AT1拮抗剂氯沙坦治疗的丙型肝炎病毒介导的纤维化患者的纤维化程度进行比较。
结果：组成性的P - Ser(536) - RelA是人类肝肌成纤维细胞的一个特征，无论是在体外还是在患病肝脏的原位。自分泌血管紧张素II刺激IKK介导的RelA在Ser(536)位点的磷酸化，这对于NF - κB的核转运和转录活性是必需的。抑制血管紧张素II、血管紧张素II 1型受体（AT1）或IKK可阻断Ser(536)磷酸化并刺激肌成纤维细胞凋亡。用血管紧张素转换酶（ACE）抑制剂卡托普利或IKK抑制剂柳氮磺胺吡啶治疗纤维化的啮齿动物肝脏，导致P - Ser(536) - RelA阳性肌成纤维细胞减少和纤维化消退。在人类肝脏样本中，P - Ser(536) - RelA阳性细胞数量增加与暴露于氯沙坦后消退的纤维化相关。
结论：包括血管紧张素II、IKK和P - Ser(536) - RelA的自分泌途径调节肌成纤维细胞的存活，并且可作为靶点来刺激肝脏纤维化的治疗性消退。
Background & AimS: The transcription factor nuclear factor-kappa B (NF)-kappa B promotes survival of hepatic myofibroblasts and fibrogenesis through poorly defined mechanisms. We investigated the activities of angiotensin II and I kappa B kinase (IKK) in regulation of NF-kappa B activity and the role of these proteins in liver fibrosis in rodents and humans. Methods: Phosphorylation of the NF-kappa B subunit RelA at serine 536 (P-Ser(536)-RelA) was detected by immunoblot and immunohistochemical analyses. P-Ser(536)-RelA function was assessed using vectors that expressed mutant forms of RelA, cell-permeable blocking peptides, and assays for RelA nuclear transport and apoptosis. Levels of P-Ser(536)-RelA were compared with degree of fibrosis in liver sections from chronically injured rats and patients with hepatitis C virus-mediated fibrosis who had been treated with the AT1 antagonist losartan. Results: Constitutive P-Ser(536)-RelA is a feature of human hepatic myofibroblasts, both in vitro and in situ in diseased livers. Autocrine angiotensin II stimulated IKK-mediated phosphorylation of RelA at Ser(536), which was required for nuclear transport and transcriptional activity of NF-kappa B. Inhibition of angiotensin II, the angiotensin II receptor type 1 (AT1), or IKK blocked Ser(536) phosphorylation and stimulated myofibroblast apoptosis. Treatment of fibrotic rodent liver with the angiotensin converting enzyme (ACE) inhibitor captopril or the IKK inhibitor sulphasalazine resulted in loss of P-Ser(536)-RelA-positive myofibroblasts and fibrosis regression. In human liver samples, increased numbers of P-Ser(536)-RelA-positive cells were associated with fibrosis that regressed following exposure to losartan. Conclusions: An autocrine pathway that includes angiotensin II, IKK, and P-Ser(536)-RelA regulates myofibroblast survival and can be targeted to stimulate therapeutic regression of liver fibrosis.