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Background <p>Cardiac fibrosis exerts a lasting influence on the development of heart failure (HF), whereas there is no specific and effective therapeutic strategy to combat cardiac fibrosis.</p> Objectives <p>CUGBP Elav-like family member 4 (CELF4), an RNA-binding protein, influences tumor progression through post-transcription regulation, while the role of CELF4 in HF remains elusive.</p> Methods <p>Transverse aortic constriction (TAC) was applied to induce pressure overload-induced cardiac remodeling in 6-week-old male mice. Global CELF4 knockout (CELF4<sup>−/−</sup>) mice were generated and littermate wild-type (CELF4<sup>+/+</sup>) mice were used as control. Primary mouse cardiac fibroblasts (CFs) were isolated and used to determine the cellular and molecular mechanisms of CELF4.</p> Results <p>The mRNA expression of CELF4 was significantly upregulated in mouse failing heart after TAC. In vitro experiments showed that CELF4 was specifically induced by TGF-β1 in CFs, but no change was observed in cardiomyocytes. CELF4 deficiency attenuated cardiac fibrosis and preserved the functions of pressure overload-induced hearts. We observed that depletion of CELF4 markedly reduced CF proliferation and migration induced by TGF-β1. Furthermore, depletion of CELF4 alleviated Collagen I and α-SMA expression in CFs as determined by western blots. Using RNA pull-down and Luciferase assay, we found an intrinsic binding of CELF4 with 3‘UTR of flavin containing monooxygenase 2 (FMO2), which blunted the phosphorylation of Smad2/3 in CFs after TGF-β1 stimulation.</p> Conclusion <p><?tk 2?>Our study delineates that decreased CELF4 retards cardiac fibrosis and HF via interaction with FMO2 and suppression of Smad2/3 signaling. Inhibition of CELF4 may become a potential therapy target for cardiac fibrosis and HF.</p>

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CUGBP Elav-like family member 4 promotes cardiac remodeling through Inhibition of FMO2

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月3日

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  • Xianlin Zhang,
  • Jun Wang,
  • Jinlong Li,
  • Qiao Lu,
  • Wenhui Xu,
  • Jianhui Zhuang,
  • Bi Tang

摘要

Background

Cardiac fibrosis exerts a lasting influence on the development of heart failure (HF), whereas there is no specific and effective therapeutic strategy to combat cardiac fibrosis.

Objectives

CUGBP Elav-like family member 4 (CELF4), an RNA-binding protein, influences tumor progression through post-transcription regulation, while the role of CELF4 in HF remains elusive.

Methods

Transverse aortic constriction (TAC) was applied to induce pressure overload-induced cardiac remodeling in 6-week-old male mice. Global CELF4 knockout (CELF4−/−) mice were generated and littermate wild-type (CELF4+/+) mice were used as control. Primary mouse cardiac fibroblasts (CFs) were isolated and used to determine the cellular and molecular mechanisms of CELF4.

Results

The mRNA expression of CELF4 was significantly upregulated in mouse failing heart after TAC. In vitro experiments showed that CELF4 was specifically induced by TGF-β1 in CFs, but no change was observed in cardiomyocytes. CELF4 deficiency attenuated cardiac fibrosis and preserved the functions of pressure overload-induced hearts. We observed that depletion of CELF4 markedly reduced CF proliferation and migration induced by TGF-β1. Furthermore, depletion of CELF4 alleviated Collagen I and α-SMA expression in CFs as determined by western blots. Using RNA pull-down and Luciferase assay, we found an intrinsic binding of CELF4 with 3‘UTR of flavin containing monooxygenase 2 (FMO2), which blunted the phosphorylation of Smad2/3 in CFs after TGF-β1 stimulation.

Conclusion

Our study delineates that decreased CELF4 retards cardiac fibrosis and HF via interaction with FMO2 and suppression of Smad2/3 signaling. Inhibition of CELF4 may become a potential therapy target for cardiac fibrosis and HF.