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

Author:

Elnagdy Mohamed123,Wang Yali124,Rodriguez Walter124,Zhang JingWen125,Bauer Philip46,Wilkey Daniel W25,Merchant Michael1235,Pan Jianmin7,Farooqui Zainab5,Cannon Robert8,Rai Shesh127,Maldonado Claudio46,Barve Shirish1235,McClain Craig J12359,Gobejishvili Leila12345ORCID

Affiliation:

1. University of Louisville Alcohol Research Center Louisville KY USA

2. Hepatobiology and Toxicology Center Louisville KY USA

3. Department of Pharmacology and Toxicology School of Medicine Louisville KY USA

4. Department of Physiology School of Medicine, University of Louisville Louisville KY USA

5. Department of Medicine School of Medicine Louisville KY USA

6. EndoProtech, Inc Louisville KY USA

7. Department of Bioinformatics and Biostatistics School of Public Health and Information Sciences Louisville KY USA

8. Department of Surgery University of Alabama at Birmingham Birmingham AL USA

9. Robley Rex VA Medical Center Louisville KY USA

Abstract

AbstractActivation 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.

Funder

National Institutes of Health

Publisher

Wiley

Subject

Pathology and Forensic Medicine

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