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Background <p>Pathological cardiac hypertrophy serves as a key pathological precursor to heart failure (HF) and represents a major public health challenge worldwide. Although its clinical importance is well recognized, the underlying mechanism remains incompletely understood. Growing evidence suggests that circular RNAs (circRNAs) play significant roles in the development of cardiac pathologies. Nevertheless, the specific biological functions and regulatory mechanisms of circRNAs in cardiac hypertrophy and HF are still largely unknown. This study aimed to explore the functional role of circCDR1as in cardiac hypertrophy and elucidate its underlying molecular mechanisms.</p> Methods <p>The role of circCDR1as in myocardial hypertrophy was examined using a mouse model of pressure overload-induced hypertrophy established by transverse aortic constriction (TAC). Mass spectrometry analysis following RNA pull-down was used to identify (sarcoplasmic/endoplasmic reticulum Ca<sup>2+</sup>-ATPase 2A) SERCA2a as an interacting protein of circCDR1as. To clarify the molecular mechanism by which circCDR1as regulates SERCA2a, protein synthesis and degradation inhibitors were used to verify the cause of SERCA2a downregulation during pathological cardiac hypertrophy.</p> Results <p>circCDR1as was upregulated in the blood of patients with cardiac hypertrophy and could be an independent risk factor for cardiac hypertrophy. Experiments in mice suggested that knockdown of circCDR1as ameliorated cardiac dysfunction and attenuated myocardial hypertrophy after TAC surgery. Conversely, the overexpression of circCDR1as mediated by the 9 adeno-associated virus (AAV9) induced hypertrophic growth and led to HF. Moreover, circCDR1as promotes an increase in the surface area of neonatal mouse cardiomyocytes (NMCMs). Mechanistically, circCDR1as promotes cardiac hypertrophy and HF by binding to SERCA2a, enhancing its NEDD4L-mediated K48-linked ubiquitination and proteasomal degradation, thereby disrupting calcium homeostasis in cardiomyocytes.</p> Conclusions <p>These findings identify circCDR1as as a potential pathological biomarker of cardiac hypertrophy and highlight its potential as a therapeutic target for treating hypertrophic cardiomyopathy. The current clinical observations are still preliminary and require validation in larger cohorts and in human myocardial tissues.</p>

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The functional role of the circular RNA circCDR1as targeting SERCA2a in the progression of pathological cardiac hypertrophy and heart failure

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月25日

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  • Jiapan Wang,
  • Wenjie Liao,
  • Hongda Li,
  • Zhenru Wang,
  • Xingda Li,
  • Xiuye Zhao,
  • Peifeng Li,
  • Mingxiu Zhang,
  • Chunlei Duan,
  • Jia Wang,
  • Changling Lv,
  • Zhen Chen,
  • Haonan Du,
  • Xueqi He,
  • Xinyuan Hao,
  • Yu Zhang,
  • Yan Zhang,
  • Ye Yuan,
  • Zhimin Du

摘要

Background

Pathological cardiac hypertrophy serves as a key pathological precursor to heart failure (HF) and represents a major public health challenge worldwide. Although its clinical importance is well recognized, the underlying mechanism remains incompletely understood. Growing evidence suggests that circular RNAs (circRNAs) play significant roles in the development of cardiac pathologies. Nevertheless, the specific biological functions and regulatory mechanisms of circRNAs in cardiac hypertrophy and HF are still largely unknown. This study aimed to explore the functional role of circCDR1as in cardiac hypertrophy and elucidate its underlying molecular mechanisms.

Methods

The role of circCDR1as in myocardial hypertrophy was examined using a mouse model of pressure overload-induced hypertrophy established by transverse aortic constriction (TAC). Mass spectrometry analysis following RNA pull-down was used to identify (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2A) SERCA2a as an interacting protein of circCDR1as. To clarify the molecular mechanism by which circCDR1as regulates SERCA2a, protein synthesis and degradation inhibitors were used to verify the cause of SERCA2a downregulation during pathological cardiac hypertrophy.

Results

circCDR1as was upregulated in the blood of patients with cardiac hypertrophy and could be an independent risk factor for cardiac hypertrophy. Experiments in mice suggested that knockdown of circCDR1as ameliorated cardiac dysfunction and attenuated myocardial hypertrophy after TAC surgery. Conversely, the overexpression of circCDR1as mediated by the 9 adeno-associated virus (AAV9) induced hypertrophic growth and led to HF. Moreover, circCDR1as promotes an increase in the surface area of neonatal mouse cardiomyocytes (NMCMs). Mechanistically, circCDR1as promotes cardiac hypertrophy and HF by binding to SERCA2a, enhancing its NEDD4L-mediated K48-linked ubiquitination and proteasomal degradation, thereby disrupting calcium homeostasis in cardiomyocytes.

Conclusions

These findings identify circCDR1as as a potential pathological biomarker of cardiac hypertrophy and highlight its potential as a therapeutic target for treating hypertrophic cardiomyopathy. The current clinical observations are still preliminary and require validation in larger cohorts and in human myocardial tissues.