دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Increased expression of phosphodiesterase 4 in activated hepatic stellate cells promotes cytoskeleton remodeling and cell migration.
المؤلفون: Elnagdy M; University of Louisville Alcohol Research Center, Louisville, KY, USA.; Hepatobiology and Toxicology Center, Louisville, KY, USA.; Department of Pharmacology and Toxicology, School of Medicine, Louisville, KY, USA., Wang Y; University of Louisville Alcohol Research Center, Louisville, KY, USA.; Hepatobiology and Toxicology Center, Louisville, KY, USA.; Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, USA., Rodriguez W; University of Louisville Alcohol Research Center, Louisville, KY, USA.; Hepatobiology and Toxicology Center, Louisville, KY, USA.; Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, USA., Zhang J; University of Louisville Alcohol Research Center, Louisville, KY, USA.; Hepatobiology and Toxicology Center, Louisville, KY, USA.; Department of Medicine, School of Medicine, Louisville, KY, USA., Bauer P; Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, USA.; EndoProtech, Inc, Louisville, KY, USA., Wilkey DW; Hepatobiology and Toxicology Center, Louisville, KY, USA.; Department of Medicine, School of Medicine, Louisville, KY, USA., Merchant M; University of Louisville Alcohol Research Center, Louisville, KY, USA.; Hepatobiology and Toxicology Center, Louisville, KY, USA.; Department of Pharmacology and Toxicology, School of Medicine, Louisville, KY, USA.; Department of Medicine, School of Medicine, Louisville, KY, USA., Pan J; Department of Bioinformatics and Biostatistics, School of Public Health and Information Sciences, Louisville, KY, USA., Farooqui Z; Department of Medicine, School of Medicine, Louisville, KY, USA., Cannon R; Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA., Rai S; University of Louisville Alcohol Research Center, Louisville, KY, USA.; Hepatobiology and Toxicology Center, Louisville, KY, USA.; Department of Bioinformatics and Biostatistics, School of Public Health and Information Sciences, Louisville, KY, USA., Maldonado C; Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, USA.; EndoProtech, Inc, Louisville, KY, USA., Barve S; University of Louisville Alcohol Research Center, Louisville, KY, USA.; Hepatobiology and Toxicology Center, Louisville, KY, USA.; Department of Pharmacology and Toxicology, School of Medicine, Louisville, KY, USA.; Department of Medicine, School of Medicine, Louisville, KY, USA., McClain CJ; University of Louisville Alcohol Research Center, Louisville, KY, USA.; Hepatobiology and Toxicology Center, Louisville, KY, USA.; Department of Pharmacology and Toxicology, School of Medicine, Louisville, KY, USA.; Department of Medicine, School of Medicine, Louisville, KY, USA.; Robley Rex VA Medical Center, Louisville, KY, USA., Gobejishvili L; University of Louisville Alcohol Research Center, Louisville, KY, USA.; Hepatobiology and Toxicology Center, Louisville, KY, USA.; Department of Pharmacology and Toxicology, School of Medicine, Louisville, KY, USA.; Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, USA.; Department of Medicine, School of Medicine, Louisville, KY, USA.
المصدر: The Journal of pathology [J Pathol] 2023 Nov; Vol. 261 (3), pp. 361-371. Date of Electronic Publication: 2023 Sep 21.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: John Wiley And Sons Country of Publication: England NLM ID: 0204634 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-9896 (Electronic) Linking ISSN: 00223417 NLM ISO Abbreviation: J Pathol Subsets: MEDLINE
أسماء مطبوعة: Publication: Chichester : John Wiley And Sons
Original Publication: London, Oliver & Boyd.
مواضيع طبية MeSH: Actins*/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 4*/genetics , Cyclic Nucleotide Phosphodiesterases, Type 4*/metabolism, Animals ; Humans ; Mice ; Cell Movement ; Cytoskeleton/metabolism ; Cytoskeleton/pathology ; Fibrosis ; Hepatic Stellate Cells/metabolism ; Liver Cirrhosis/pathology ; Proteomics ; Rolipram/metabolism
مستخلص: 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.
(© 2023 The Pathological Society of Great Britain and Ireland.)
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معلومات مُعتمدة: P50AA024337 United States NH NIH HHS; P20 GM113226 United States GM NIGMS NIH HHS; R01AA029798 United States NH NIH HHS; P50 AA024337 United States AA NIAAA NIH HHS; R24AAA025017 United States NH NIH HHS; R01 AA029798 United States AA NIAAA NIH HHS; R44 AA021331 United States AA NIAAA NIH HHS; R24 AA025017 United States AA NIAAA NIH HHS; R44AA021331 United States NH NIH HHS; P20GM113226 United States NH NIH HHS
فهرسة مساهمة: Keywords: cell migration; cyclic AMP signaling; cytoskeleton remodeling; hepatic stellate cells; liver fibrosis; phosphodiesterase 4; proteomics
المشرفين على المادة: 0 (Actins)
EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4)
K676NL63N7 (Rolipram)
EC 3.1.4.17 (PDE4A protein, human)
EC 3.1.4.17 (Pde4a protein, mouse)
تواريخ الأحداث: Date Created: 20230922 Date Completed: 20231122 Latest Revision: 20240404
رمز التحديث: 20240404
مُعرف محوري في PubMed: PMC10653049
DOI: 10.1002/path.6194
PMID: 37735782
قاعدة البيانات: MEDLINE
الوصف
تدمد:1096-9896
DOI:10.1002/path.6194