Aldosterone induction of hepatic stellate cell contraction through activation of RhoA/ROCK-2 signaling pathway
Aldosterone induction of hepatic stellate cell contraction through activation of RhoA/ROCK-2 signaling pathway
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DOI：
10.1016/j.regpep.2011.04.010
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发表时间：
2011-08-08
影响因子：
--
通讯作者：
Li, Xu
中科院分区：
文献类型：
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作者：
Ji, Hongli;Meng, Ying;Li, Xu
RhoA/ROCK-2 信号通路对于激活的肝星状细胞 (HSC) 收缩是必需的。 HSC收缩在肝硬化和门脉高压的发病机制中发挥着重要作用。本研究调查了醛固酮是否通过激活 RhoA/ROCK-2 信号通路促进 HSC 收缩。通过原位链霉蛋白酶/胶原酶灌注从 Sprague-Dawley 大鼠中分离原代 HSC。我们发现醛固酮增强了接种 HSC 的胶原蛋白晶格的收缩。这种诱导的收缩可被盐皮质激素受体 (MR) 抑制剂螺内酯、ROCK-2 抑制剂 Y27632 和血管紧张素 II 1 型受体 (AT(1)R) 抑制剂厄贝沙坦抑制。此外，肌动蛋白纤维染色显示醛固酮显着增加HSC中肌动蛋白纤维的形成。与螺内酯、Y27632 或厄贝沙坦预孵育可抑制醛固酮诱导的肌动蛋白纤维重组。从分子上讲，醛固酮对 HSC 收缩激活的影响是由磷酸化肌球蛋白轻链 (P-MLC) 通过 RhoA/ROCK-2 信号通路介导的。所有这些抑制剂都能够阻断 HSC 中 RhoA/ROCK-2/P-MLC 级联中醛固酮诱导的蛋白表达。综上所述，我们目前的研究表明醛固酮通过激活 RhoA/ROCK-2 信号通路诱导活化的 HSC 收缩。这一发现可能为控制肝硬化和门静脉高压提供潜在的治疗靶点。 (C) 2011 Elsevier B.V. 保留所有权利。
The RhoA/ROCK-2 signaling pathway is necessary for activated hepatic stellate cell (HSC) contraction. HSC contraction plays an important role in the pathogenesis of cirrhosis and portal hypertension. This study investigated whether aldosterone contributes to HSC contraction by activation of the RhoA/ROCK-2 signaling pathway. Primary HSCs were isolated from Sprague-Dawley rats via in situ pronase/collagenase perfusion. We found that aldosterone enhanced the contraction of a collagen lattice seeded with HSCs. This induced contraction was suppressed by the mineralcorticoid receptor (MR) inhibitor spironolactone, the ROCK-2 inhibitor Y27632, and the angiotensin II type 1 receptor (AT(1)R) inhibitor irbesartan. Moreover, actin fiber staining showed that aldosterone significantly increased actin fiber formation in HSCs. Pre-incubating with spironolactone, Y27632, or irbesartan inhibited the aldosterone-induced actin fiber reorganization. Molecularly, the effect of aldosterone on activation of HSC contraction was mediated by phosphorylated myosin light chain (P-MLC) through the RhoA/ROCK-2 signaling pathway. All these inhibitors had the ability to block aldosterone-induced protein expressions in the RhoA/ROCK-2/P-MLC cascade in HSCs. Taken together, our current study suggests that aldosterone induces contraction of activated HSCs through the activation of the RhoA/ROCK-2 signaling pathway. This finding may provide a potential therapeutic target for control of cirrhosis and portal hypertension. (C) 2011 Elsevier B.V. All rights reserved.