Increased expression of phosphodiesterase 4 in activated hepatic stellate cells promotes cytoskeleton remodeling and cell migration

细胞生物学 肝星状细胞 罗亚 肌动蛋白细胞骨架 鸟嘌呤核苷酸交换因子 细胞骨架 细胞迁移 焦点粘着 生物 Rho相关蛋白激酶 化学 信号转导 细胞 内分泌学 生物化学
作者
Mohamed Elnagdy,Yali Wang,Walter Rodríguez,Jingwen Zhang,Philip M. Bauer,Daniel W. Wilkey,Michael L. Merchant,Jianmin Pan,Zainab Farooqui,Robert M. Cannon,Shesh Rai,Claudio Maldonado,Shirish Barve,Craig J. McClain,Leila Gobejishvili
标识
DOI:10.1002/path.6194
摘要

Abstract Activation and transdifferentiation of hepatic stellate cells (HSC) into migratory myofibroblasts is a key process in liver fibrogenesis. Cell migration requires an active remodeling of the cytoskeleton, which is a tightly regulated process coordinated by Rho‐specific guanine nucleotide exchange factors (GEFs) and the Rho family of small GTPases. Rho‐associated kinase (ROCK) promotes assembly of focal adhesions and actin stress fibers by regulating cytoskeleton organization. GEF exchange protein directly activated by cAMP 1 (EPAC1) has been implicated in modulating TGFβ1 and Rho signaling; however, its role in HSC migration has never been examined. The aim of this study was to evaluate the role of cAMP‐degrading phosphodiesterase 4 (PDE4) enzymes in regulating EPAC1 signaling, HSC migration, and fibrogenesis. We show that PDE4 protein expression is increased in activated HSCs expressing alpha smooth muscle actin and active myosin light chain (MLC) in fibrotic tissues of human nonalcoholic steatohepatitis cirrhosis livers and mouse livers exposed to carbon tetrachloride. In human livers, TGFβ1 levels were highly correlated with PDE4 expression. TGFβ1 treatment of LX2 HSCs decreased levels of cAMP and EPAC1 and increased PDE4D expression. PDE4 specific inhibitor, rolipram, and an EPAC‐specific agonist decreased TGFβ1‐mediated cell migration in vitro . In vivo , targeted delivery of rolipram to the liver prevented fibrogenesis and collagen deposition and decreased the expression of several fibrosis‐related genes, and HSC activation. Proteomic analysis of mouse liver tissues identified the regulation of actin cytoskeleton by the kinase effectors of Rho GTPases as a major pathway impacted by rolipram. Western blot analyses confirmed that PDE4 inhibition decreased active MLC and endothelin 1 levels, key proteins involved in cytoskeleton remodeling and contractility. The current study, for the first time, demonstrates that PDE4 enzymes are expressed in hepatic myofibroblasts and promote cytoskeleton remodeling and HSC migration. © 2023 The Pathological Society of Great Britain and Ireland.
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