Inhibition of pancreatic stellate cell activation by the hydroxymethylglutaryl coenzyme A reductase inhibitor lovastatin
Inhibition of pancreatic stellate cell activation by the hydroxymethylglutaryl coenzyme A reductase inhibitor lovastatin
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DOI：
10.1016/s0006-2952(03)00075-3
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发表时间：
2003-04-15
影响因子：
5.8
通讯作者：
Liebe, S
中科院分区：
文献类型：
--
作者：
Jaster, R;Brock, P;Liebe, S
胰腺星状细胞（PSC）在胰腺纤维化中起关键作用，这是慢性胰腺炎的一个恒定特征。PSC活化响应于促纤维化介质如细胞因子而发生，并且涉及增殖、向成肌纤维细胞表型转变和细胞外基质蛋白的产生增强。以前，我们已经证明PSC激活与Ras-Raf-ERK（细胞外信号调节激酶）信号级联的活性相关[Gut 51（2002）579]。使用大鼠培养模型的PSC，我们现在已经评估了洛伐他汀，羟甲基戊二酰辅酶A还原酶抑制剂，干扰蛋白质异戊二烯化，对PSC的活力和激活，以及信号通过Ras蛋白的影响。应用TUNEL法检测凋亡细胞。使用溴脱氧尿苷DNA掺入测定定量PSC的增殖。通过免疫印迹分析α-平滑肌肌动蛋白（成肌纤维细胞表型的指标）的表达、ERK活化和Ras超家族成员RhoA的膜易位。洛伐他汀以剂量依赖性方式抑制血清和血小板源性生长因子刺激的PSC增殖。在药物浓度高于生长抑制所需的水平时，观察到凋亡细胞的强烈增加。此外，在原代培养过程中，洛伐他汀抑制α-平滑肌肌动蛋白表达的诱导。Inummoblot实验表明，洛伐他汀抑制Ras介导的ERK 1/2激活和血小板源性生长因子诱导的RhoA膜转位。总之，我们的数据表明，洛伐他汀，通过中断Ras信号，干扰PSC激活。他汀类药物的抗肝纤维化效果应在慢性胰腺炎动物模型中进行测试。(C)2003年爱思唯尔科学公司All rights reserved.
Pancreatic stellate cells (PSCs) play a key role in pancreatic fibrosis, a constant feature of chronic pancreatitis. PSC activation occurs in response to profibrogenic mediators such as cytokines and involves proliferation, transition towards a myofibroblastic phenotype and enhanced production of extracellular matrix proteins. Previously, we have shown that PSC activation correlates with the activity of the Ras-Raf-ERK (extracellular signal-regulated kinase) signalling cascade [Gut 51 (2002) 579]. Using a rat culture model of PSCs, we have now evaluated the effects of lovastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor that interferes with protein isoprenylation, on PSC viability and activation as well as on signalling through Ras proteins. Apoptotic cells were detected applying the TUNEL assay. Proliferation of PSCs was quantitated using the bromodeoxyuridine DNA incorporation assay. Expression of alpha-smooth muscle actin (an indicator of the myofibroblastic phenotype), ERK activation and membrane translocation of the Ras superfamily member RhoA were analysed by immunoblotting. Lovastatin inhibited serum- and platelet-derived growth factor-stimulated PSC proliferation in a dose-dependent manner. At drug concentrations above the level required for growth inhibition, a strong increase of apoptotic cells was observed. Furthermore, lovastatin inhibited induction of alpha-smooth muscle actin expression in the course of primary culture. Inummoblot experiments indicated that lovastatin suppressed both Ras-mediated ERK 1/2 activation and platelet-derived growth factor-induced membrane translocation of RhoA. Together, our data suggest that lovastatin, through the interruption of Ras signalling, interferes with PSC activation. The antifibrotic efficiency of statins should be tested in animal models of chronic pancreatitis. (C) 2003 Elsevier Science Inc. All rights reserved.