HuR-dependent expression of Wisp1 is necessary for TGFβ-induced cardiac myofibroblast activity.

Autor: Green LC; Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America; Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America., Slone S; Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America; Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America., Anthony SR; Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America., Guarnieri AR; Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America., Parkins S; Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America., Shearer SM; Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America; Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America., Nieman ML; Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America., Roy S; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, United States of America., Aube J; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, United States of America., Wu X; Department of Molecular Biosciences, University of Kansas, Lawrence, KS, United States of America., Xu L; Department of Molecular Biosciences, University of Kansas, Lawrence, KS, United States of America., Kanisicak O; Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America., Tranter M; Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America. Electronic address: Michael.Tranter@UC.edu.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2023 Jan; Vol. 174, pp. 38-46. Date of Electronic Publication: 2022 Nov 11.
DOI: 10.1016/j.yjmcc.2022.10.007
Abstrakt: 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.
Competing Interests: Declaration of Competing Interest None.
(Copyright © 2022. Published by Elsevier Ltd.)
Databáze: MEDLINE
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