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Cell migration requires an active remodeling of the cytoskeleton, which is a tightly regulated process coordinated by Rho\u2010specific guanine nucleotide exchange factors (GEFs) and the Rho family of small GTPases. Rho\u2010associated 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 TGF\u03b21 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\u2010degrading 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, TGF\u03b21 levels were highly correlated with PDE4 expression. TGF\u03b21 treatment of LX2 HSCs decreased levels of cAMP and EPAC1 and increased PDE4D expression. PDE4 specific inhibitor, rolipram, and an EPAC\u2010specific agonist decreased TGF\u03b21\u2010mediated cell migration <jats:italic>in vitro<\/jats:italic>. <jats:italic>In vivo<\/jats:italic>, targeted delivery of rolipram to the liver prevented fibrogenesis and collagen deposition and decreased the expression of several fibrosis\u2010related 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. \u00a9 2023 The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6194","type":"journal-article","created":{"date-parts":[[2023,9,22]],"date-time":"2023-09-22T00:18:27Z","timestamp":1695341907000},"page":"361-371","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Increased expression of phosphodiesterase 4 in activated hepatic stellate cells promotes cytoskeleton remodeling and cell migration"],"prefix":"10.1002","volume":"261","author":[{"given":"Mohamed","family":"Elnagdy","sequence":"first","affiliation":[{"name":"University of Louisville Alcohol Research Center  Louisville KY USA"},{"name":"Hepatobiology and Toxicology Center  Louisville KY USA"},{"name":"Department of Pharmacology and Toxicology School of Medicine  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