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<p>Ischaemic heart disease is an important cause of death in humans, and resupply of blood to damaged myocardium can exacerbate the risk of cardiac I/R injury. Circular RNAs (circRNAs) play an important role in cardiovascular disease. In this study we investigated the regulatory role of circDhx32 in the progression of I/R injury. Cardiac I/R model was established in mice by ligating the left anterior descending coronary artery (LAD) for 45 min, followed by blood reperfusion for 24 h or 2 weeks. For in vitro study, neonatal mouse ventricular cardiomyocytes were subjected to hypoxia-reoxygenation (H/R) assault. CircDhx32 was significantly upregulated in I/R-treated mice and H/R-treated cardiomyocytes. Cardiomyocyte-specific knockdown of circDhx32 ameliorated the pathological outcomes of cardiac I/R injury including improved cardiac function, reduced infarct size and reduced release of cardiac injury biomarkers. The protective effects of circDhx32 silencing were also observed in cardiomyocytes after H/R. We demonstrated that ALKBH5 functioned as an m<sup>6</sup>A demethylase, removing the m<sup>6</sup>A modification sites of circDhx32. Reduced m<sup>6</sup>A modification inhibited recognition and bindin<Emphasis Type="Underline">g</Emphasis> by the m<sup>6</sup>A readers YTHDF2 and YTHDC1, leading to circDhx32 degradation and diminished nucleoplasmic export under pathological conditions. Elevated circDhx32 inhibited the transcriptional activation of AdipoR1 by binding to FOXO1. Conversel<Emphasis Type="Underline">y</Emphasis>, circDhx32 deficiency alleviated the inflammatory responses in I/R-treated mice and H/R-treated cardiomyocytes including decreased mRNA expression levels and release of inflammatory cytokines such as IL-6, TNF-α and IL-1β potentially through modulation of the AdipoR1-AMPK-NF-κB signaling pathway. In conclusion, ALKBH5 acted as m<sup>6</sup>A eraser accompanied by the m<sup>6</sup>A readers YTHDF2 and YTHDC1 to promote high expression and nuclear retention of circDhx32 under pathological conditions. CircDhx32 regulated the inflammatory responses to cardiac I/R injury by targeting the AdipoR1-AMPK-NF-κB signaling pathway, which competed with AdipoR1 for FOXO1. These results revea<Emphasis Type="Underline">l</Emphasis> a novel mechanism underlying cardiac ischaemic injury, and circDhx32 is expected to be a potential therapeutic target for early intervention in ischaemic cardiac disease.</p><p></p>

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Circular RNA circDhx32 promotes cardiac inflammatory responses in mouse cardiac ischemia-reperfusion injury via binding to FOXO1 competed with AdipoR1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月17日

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  • Wei Si,
  • Chun-lei Wang,
  • Ling-hua Zeng,
  • Qiao-yue Zhao,
  • Ya-ting Xie,
  • Yang Yang,
  • Hong-tao Diao,
  • Jing-lun Song,
  • Han Wu,
  • Feng Zhang,
  • Zhuo Wang,
  • Xue Kong,
  • Wei-tao Jiang,
  • Xin-yue Zhang,
  • Ke-ying Lin,
  • Fang-ting Yao,
  • Yu-ting Xiong,
  • Teng-fei Pan,
  • Ping Pang,
  • Bao-feng Yang,
  • Yu Bian

摘要

Ischaemic heart disease is an important cause of death in humans, and resupply of blood to damaged myocardium can exacerbate the risk of cardiac I/R injury. Circular RNAs (circRNAs) play an important role in cardiovascular disease. In this study we investigated the regulatory role of circDhx32 in the progression of I/R injury. Cardiac I/R model was established in mice by ligating the left anterior descending coronary artery (LAD) for 45 min, followed by blood reperfusion for 24 h or 2 weeks. For in vitro study, neonatal mouse ventricular cardiomyocytes were subjected to hypoxia-reoxygenation (H/R) assault. CircDhx32 was significantly upregulated in I/R-treated mice and H/R-treated cardiomyocytes. Cardiomyocyte-specific knockdown of circDhx32 ameliorated the pathological outcomes of cardiac I/R injury including improved cardiac function, reduced infarct size and reduced release of cardiac injury biomarkers. The protective effects of circDhx32 silencing were also observed in cardiomyocytes after H/R. We demonstrated that ALKBH5 functioned as an m6A demethylase, removing the m6A modification sites of circDhx32. Reduced m6A modification inhibited recognition and binding by the m6A readers YTHDF2 and YTHDC1, leading to circDhx32 degradation and diminished nucleoplasmic export under pathological conditions. Elevated circDhx32 inhibited the transcriptional activation of AdipoR1 by binding to FOXO1. Conversely, circDhx32 deficiency alleviated the inflammatory responses in I/R-treated mice and H/R-treated cardiomyocytes including decreased mRNA expression levels and release of inflammatory cytokines such as IL-6, TNF-α and IL-1β potentially through modulation of the AdipoR1-AMPK-NF-κB signaling pathway. In conclusion, ALKBH5 acted as m6A eraser accompanied by the m6A readers YTHDF2 and YTHDC1 to promote high expression and nuclear retention of circDhx32 under pathological conditions. CircDhx32 regulated the inflammatory responses to cardiac I/R injury by targeting the AdipoR1-AMPK-NF-κB signaling pathway, which competed with AdipoR1 for FOXO1. These results reveal a novel mechanism underlying cardiac ischaemic injury, and circDhx32 is expected to be a potential therapeutic target for early intervention in ischaemic cardiac disease.