KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins
KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins
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DOI：
10.1136/gutjnl-2014-308338
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发表时间：
2015-09-01
期刊：
影响因子：
24.5
通讯作者：
Gracia-Sancho, Jordi
中科院分区：
文献类型：
--
作者：
Marrone, Giusi;Maeso-Diaz, Raquel;Gracia-Sancho, Jordi
目的肝脏在肝硬化早期诱导转录因子kruppel样因子2 (KLF2)，以减轻血管功能障碍的发生；然而，其内源性表达结果不足以减轻门静脉高压症的建立和肝硬化的加重。在此，我们旨在探讨肝脏KLF2过表达在体外和体内肝硬化模型中的作用及其潜在机制。在存在/不存在KLF2抑制剂的情况下，用KLF2药理诱导剂辛伐他汀，用腺病毒编码该转录因子（Ad-KLF2）或载体，对人和大鼠肝硬化肝星状细胞（HSC）进行激活表型评估。研究了过表达KLF2的实质细胞和非实质细胞之间可能的旁分泌相互作用。在肝硬化大鼠中评估体内KLF2过表达对肝纤维化和全身及肝脏血流动力学的影响。结果KLF2的上调在一定程度上通过激活核因子(NF)- e2相关因子2 (Nrf2)，深刻地改善了HSC表型（减少了a-平滑肌肌动蛋白、前胶原I和氧化应激）。共培养实验表明，HSC表型的改善可能通过血管内皮生长因子介导的机制改善肝窦内皮细胞。未观察到肝细胞和HSC之间的旁分泌相互作用。用辛伐他汀或Ad-KLF2治疗的肝硬化大鼠显示肝脏KLF2-Nrf2通路上调，HSC失活，肝纤维化明显减少。肝脏KLF2过表达与门静脉压力降低（-15%）相关，这是由于门静脉血流增加和肝血管阻力的减弱，以及肝内皮功能障碍的显著改善。结论外源性肝脏KLF2上调可改善肝硬化肝纤维化、内皮功能障碍和门静脉高压症。
Objective In the liver, the transcription factor, Kruppel-like factor 2 (KLF2), is induced early during progression of cirrhosis to lessen the development of vascular dysfunction; nevertheless, its endogenous expression results insufficient to attenuate establishment of portal hypertension and aggravation of cirrhosis. Herein, we aimed to explore the effects and the underlying mechanisms of hepatic KLF2 overexpression in in vitro and in vivo models of liver cirrhosis.Design Activation phenotype was evaluated in human and rat cirrhotic hepatic stellate cells (HSC) treated with the pharmacological inductor of KLF2 simvastatin, with adenovirus codifying for this transcription factor (Ad-KLF2), or vehicle, in presence/absence of inhibitors of KLF2. Possible paracrine interactions between parenchymal and non-parenchymal cells overexpressing KLF2 were studied. Effects of in vivo hepatic KLF2 overexpression on liver fibrosis and systemic and hepatic haemodynamics were assessed in cirrhotic rats.Results KLF2 upregulation profoundly ameliorated HSC phenotype (reduced a-smooth muscle actin, procollagen I and oxidative stress) partly via the activation of the nuclear factor (NF)-E2-related factor 2 (Nrf2). Coculture experiments showed that improvement in HSC phenotype paracrinally ameliorated liver sinusoidal endothelial cells probably through a vascular endothelial growth factor-mediated mechanism. No paracrine interactions between hepatocytes and HSC were observed. Cirrhotic rats treated with simvastatin or Ad-KLF2 showed hepatic upregulation in the KLF2-Nrf2 pathway, deactivation of HSC and prominent reduction in liver fibrosis. Hepatic KLF2 overexpression was associated with lower portal pressure (-15%) due to both attenuations in the increased portal blood flow and hepatic vascular resistance, together with a significant improvement in hepatic endothelial dysfunction.Conclusions Exogenous hepatic KLF2 upregulation improves liver fibrosis, endothelial dysfunction and portal hypertension in cirrhosis.