{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Green LC"],"funding":["American Heart Association","American Heart Association-American Stroke Association","NHLBI NIH HHS","NCI NIH HHS","National Institutes of Health"],"pagination":["38-46"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9868076"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["174"],"pubmed_abstract":["Cardiac fibrosis is regulated by the activation and phenotypic switching of quiescent cardiac fibroblasts to active myofibroblasts, which have extracellular matrix (ECM) remodeling and contractile functions which play a central role in cardiac remodeling in response to injury. Here, we show that expression and activity of the RNA binding protein HuR is increased in cardiac fibroblasts upon transformation to an active myofibroblast. Pharmacological inhibition of HuR significantly blunts the TGFβ-dependent increase in ECM remodeling genes, total collagen secretion, in vitro scratch closure, and collagen gel contraction in isolated primary cardiac fibroblasts, suggesting a suppression of TGFβ-induced myofibroblast activation upon HuR inhibition. We identified twenty-four mRNA transcripts that were enriched for HuR binding following TGFβ treatment via photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP). Eleven of these HuR-bound mRNAs also showed significant co-expression correlation with HuR, αSMA, and periostin in primary fibroblasts isolated from the ischemic-zone of infarcted mouse hearts. Of these, WNT1-inducible signaling pathway protein-1 (Wisp1; Ccn4), was the most significantly associated with HuR expression in fibroblasts. Accordingly, we found Wisp1 expression to be increased in cardiac fibroblasts isolated from the ischemic-zone of mouse hearts following ischemia/reperfusion, and confirmed Wisp1 expression to be HuR-dependent in isolated fibroblasts. Finally, addition of exogenous recombinant Wisp1 partially rescued myofibroblast-induced collagen gel contraction following HuR inhibition, demonstrating that HuR-dependent Wisp1 expression plays a functional role in HuR-dependent MF activity downstream of TGFβ. In conclusion, HuR activity is necessary for the functional activation of primary cardiac fibroblasts in response to TGFβ, in part through post-transcriptional regulation of Wisp1."],"journal":["Journal of molecular and cellular cardiology"],"pubmed_title":["HuR-dependent expression of Wisp1 is necessary for TGFβ-induced cardiac myofibroblast activity."],"pmcid":["PMC9868076"],"funding_grant_id":["R01 CA243445","R01 HL132111","16SDG27360004","R33-CA252158","PRE35230020","CDA34110117","916812","R01-HL132111","R33 CA252158","HL158671","R01-CA243445","R01 CA191785","PRE35210795","R01 HL148598","T32 HL125204","R01 HL158671","R01-CA191785","R01-HL148598"],"pubmed_authors":["Slone S","Xu L","Green LC","Kanisicak O","Aube J","Anthony SR","Shearer SM","Guarnieri AR","Roy S","Parkins S","Nieman ML","Tranter M","Wu X"],"additional_accession":[]},"is_claimable":false,"name":"HuR-dependent expression of Wisp1 is necessary for TGFβ-induced cardiac myofibroblast activity.","description":"Cardiac fibrosis is regulated by the activation and phenotypic switching of quiescent cardiac fibroblasts to active myofibroblasts, which have extracellular matrix (ECM) remodeling and contractile functions which play a central role in cardiac remodeling in response to injury. Here, we show that expression and activity of the RNA binding protein HuR is increased in cardiac fibroblasts upon transformation to an active myofibroblast. Pharmacological inhibition of HuR significantly blunts the TGFβ-dependent increase in ECM remodeling genes, total collagen secretion, in vitro scratch closure, and collagen gel contraction in isolated primary cardiac fibroblasts, suggesting a suppression of TGFβ-induced myofibroblast activation upon HuR inhibition. We identified twenty-four mRNA transcripts that were enriched for HuR binding following TGFβ treatment via photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP). Eleven of these HuR-bound mRNAs also showed significant co-expression correlation with HuR, αSMA, and periostin in primary fibroblasts isolated from the ischemic-zone of infarcted mouse hearts. Of these, WNT1-inducible signaling pathway protein-1 (Wisp1; Ccn4), was the most significantly associated with HuR expression in fibroblasts. Accordingly, we found Wisp1 expression to be increased in cardiac fibroblasts isolated from the ischemic-zone of mouse hearts following ischemia/reperfusion, and confirmed Wisp1 expression to be HuR-dependent in isolated fibroblasts. Finally, addition of exogenous recombinant Wisp1 partially rescued myofibroblast-induced collagen gel contraction following HuR inhibition, demonstrating that HuR-dependent Wisp1 expression plays a functional role in HuR-dependent MF activity downstream of TGFβ. In conclusion, HuR activity is necessary for the functional activation of primary cardiac fibroblasts in response to TGFβ, in part through post-transcriptional regulation of Wisp1.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Jan","modification":"2026-05-27T11:08:26.854Z","creation":"2025-02-18T23:26:25.877Z"},"accession":"S-EPMC9868076","cross_references":{"pubmed":["36372279"],"doi":["10.1016/j.yjmcc.2022.10.007"]}}