The transcription factor KLF2 mediates hepatic endothelial protection and paracrine endothelial-stellate cell deactivation induced by statins
The transcription factor KLF2 mediates hepatic endothelial protection and paracrine endothelial-stellate cell deactivation induced by statins
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DOI：
10.1016/j.jhep.2012.08.026
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发表时间：
2013-01-01
影响因子：
25.7
通讯作者：
Gracia-Sancho, Jorge
中科院分区：
文献类型：
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作者：
Marrone, Giusi;Russo, Lucia;Gracia-Sancho, Jorge
背景和目标：他汀类药物在肝硬化实验模型中改善肝内皮功能和肝纤维化，因此已被提议作为改善门脉高压综合征的治疗选择。他汀类药物可诱导肝窦内皮细胞（SEC）中的转录因子Kruppel样因子2（KLF 2），协调有效的血管保护反应。本研究的目的是在表征是否KLF 2介导他汀类药物衍生的hepatoprotein.Methods：表达KLF 2和其血管保护靶基因的SEC新鲜分离的控制或CCl 4-arrhythmic大鼠用四种不同的他汀类药物（阿托伐他汀，美伐他汀，辛伐他汀，和洛伐他汀），在甲羟戊酸（或车辆）的存在下，在静态或受控的剪切应力条件下。在SEC中分析KLF 2衍生的血管保护性转录程序，所述SEC用针对KLF 2的siRNA或siRNA对照转染，并与辛伐他汀孵育。高表达KLF 2的SEC对大鼠和人肝星状细胞（HSC）活化状态的旁分泌作用进行了评估。治疗6小时后观察到KLF 2上调，并伴有其血管保护程序的诱导。辛伐他汀血管保护作用在甲羟戊酸存在下被抑制，并且在生理剪切应力条件下培养的细胞中被放大。当用siRNA抑制KLF 2表达时，未观察到血管保护基因的他汀类药物依赖性诱导。SEC过度表达KLF 2诱导HSC的静止通过KLF 2一氧化氮鸟苷酸环化酶介导的旁分泌mechanism.Conclusions：上调肝内皮KLF 2衍生的转录程序，他汀类药物赋予血管保护和星状细胞失活，加强这些药物的治疗潜力，肝脏疾病的过程与内皮功能障碍。(C)2012年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Statins improve hepatic endothelial function and liver fibrosis in experimental models of cirrhosis, thus they have been proposed as therapeutic options to ameliorate portal hypertension syndrome. The transcription factor Kruppel-like factor 2 (KLF2) may be induced by statins in liver sinusoidal endothelial cells (SEC), orchestrating an efficient vasoprotective response. The present study aimed at characterizing whether KLF2 mediates statins-derived hepatic protection.Methods: Expression of KLF2 and its vasoprotective target genes was determined in SEC freshly isolated from control or CCl4-cirrhotic rats treated with four different statins (atorvastatin, mevastatin, simvastatin, and lovastatin), in the presence of mevalonate (or vehicle), under static or controlled shear stress conditions. KLF2-derived vasoprotective transcriptional programs were analyzed in SEC transfected with siRNA for KLF2 or siRNA-control, and incubated with simvastatin. Paracrine effects of SEC highly-expressing KLF2 on the activation status of rat and human hepatic stellate cells (HSC) were evaluated.Results: Statins administration to SEC induced significant upregulation of KLF2 expression. KLF2 upregulation was observed after 6 h of treatment and was accompanied by induction of its vasoprotective programs. Simvastatin vasoprotection was inhibited in the presence of mevalonate, and was magnified in cells cultured under physiological shear stress conditions. Statin-dependent induction of vasoprotective genes was not observed when KLF2 expression was muted with siRNA. SEC overexpressing KLF2 induced quiescence of HSC through a KLF2 nitric oxide guanylate cyclase-mediated paracrine mechanism.Conclusions: Upregulation of hepatic endothelial KLF2-derived transcriptional programs by statins confers vasoprotection and stellate cells deactivation, reinforcing the therapeutic potential of these drugs for liver diseases that course with endothelial dysfunction. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.