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<p>Heart failure (HF) involves pathological cardiac remodeling, including cardiomyocyte loss and dysfunction. While the RNA-binding protein CPEB4 has been linked to cardiomyocyte activation, its role in HF remains unclear. We established in vivo and in vitro models of cardiac injury using isoproterenol (ISO). An HF mouse model was induced by chronic ISO administration (10&#xa0;mg/kg/day, 3 weeks), while cellular injury was modeled by treating HL-1 atrial cardiomyocytes (HL-1) with ISO (10 µM, 48&#xa0;h). To investigate the molecular mechanisms, we employed transcriptome sequencing, qRT-PCR, and functional assays following siRNA-mediated knockdown of Cpeb4. Key endpoints included cell viability (CCK-8), apoptosis (Annexin V/7-AAD flow cytometry), and the alternative splicing of Eif4a2. In the HF mouse model, we observed significant cardiac hypertrophy and inflammatory infiltration, which correlated with a marked upregulation of Cpeb4 expression in myocardium. Notably, in vitro, siRNA-mediated knockdown of Cpeb4 significantly attenuated ISO-induced apoptosis and enhanced cell viability in HL-1 cells. Mechanistically, Cpeb4 depletion corrected the ISO-induced dysregulation of Eif4a2 alternative splicing, restoring the expression of its major isoforms and thereby ameliorating cellular injury. Additional co-knockdown experiments indicated that Eif4a2 contributes to the protective phenotype observed upon Cpeb4 inhibition. Our study identifies the Cpeb4-Eif4a2 axis as a key regulator in heart failure, with Cpeb4 associated with aberrant Eif4a2 splicing and cardiomyocyte apoptosis, suggesting a promising therapeutic target.</p>

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Cpeb4 regulates cardiomyocyte apoptosis in heart failure with association to Eif4a2 splicing modulation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月30日

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  • Changsheng Xu,
  • Jinlong Yan,
  • Qinghua Zhang

摘要

Heart failure (HF) involves pathological cardiac remodeling, including cardiomyocyte loss and dysfunction. While the RNA-binding protein CPEB4 has been linked to cardiomyocyte activation, its role in HF remains unclear. We established in vivo and in vitro models of cardiac injury using isoproterenol (ISO). An HF mouse model was induced by chronic ISO administration (10 mg/kg/day, 3 weeks), while cellular injury was modeled by treating HL-1 atrial cardiomyocytes (HL-1) with ISO (10 µM, 48 h). To investigate the molecular mechanisms, we employed transcriptome sequencing, qRT-PCR, and functional assays following siRNA-mediated knockdown of Cpeb4. Key endpoints included cell viability (CCK-8), apoptosis (Annexin V/7-AAD flow cytometry), and the alternative splicing of Eif4a2. In the HF mouse model, we observed significant cardiac hypertrophy and inflammatory infiltration, which correlated with a marked upregulation of Cpeb4 expression in myocardium. Notably, in vitro, siRNA-mediated knockdown of Cpeb4 significantly attenuated ISO-induced apoptosis and enhanced cell viability in HL-1 cells. Mechanistically, Cpeb4 depletion corrected the ISO-induced dysregulation of Eif4a2 alternative splicing, restoring the expression of its major isoforms and thereby ameliorating cellular injury. Additional co-knockdown experiments indicated that Eif4a2 contributes to the protective phenotype observed upon Cpeb4 inhibition. Our study identifies the Cpeb4-Eif4a2 axis as a key regulator in heart failure, with Cpeb4 associated with aberrant Eif4a2 splicing and cardiomyocyte apoptosis, suggesting a promising therapeutic target.