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<p>Myocardial infarction (MI) is an important risk factor of cardiovascular disease (CVD) and its incidence has been on the rise globally. Myocardial ischemia/reperfusion (I/R) injury is frequently detected in the ischemic myocardium. Recent studies have shown that ubiquitination plays an important role in the cardiac pathophysiological processes. Herein, we investigated the role and molecular mechanism of Ovarian tumor deubiquitinase 1&#xa0;(OTUD1) in I/R induced myocardial injury. It was observed that the myocardial OTUD1 was upregulated in I/R-induced heart tissues and global deletion of OTUD1 significantly ameliorated I/R induced myocardial injury and dysfunction. Similarly, silencing or overexpression OTUD1 affected the hypoxia/reoxygenation (H/R) induced cell apoptosis in cultured cardiomyocytes. Mechanistically, immunoprecipitation-mass spectrometry revealed that OTUD1 directly bound to receptor for activated C-kinase 1 (RACK1) which has been identified as a scaffold protein for multiple kinases including mitogen-activated protein kinase (MAPKs) and Inhibitor of nuclear factor kappa B kinase (IKK). OTUD1 could cleave K63-linked polyubiquitin chains to enhance RACK1 phosphorylation, thus modulating MAPKs and nuclear factor kappa B (NF-κB) signaling. Finally, silencing of RACK1 reverses OTUD1-promoted H/R induced myocardial apoptosis. In conclusion, our findings suggest that OTUD1 promotes I/R-induced heart injury by deubiquitinating RACK1, suggesting that OTUD1 is a potential therapeutic target for myocardial I/R.</p><p></p>

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OTUD1 deficiency attenuates myocardial ischemia/reperfusion induced cardiomyocyte apoptosis by regulating RACK1 phosphorylation

  • 期刊论文

  • 发表日期：

    2025年5月20日

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  • Yue Luo,
  • Wei-xin Li,
  • Qing-song Zheng,
  • Jue-qian Yan,
  • Yu-die Yang,
  • Si-rui Shen,
  • Qian-hui Zhang,
  • Guang Liang,
  • Yi Wang,
  • Ding-dao Chen,
  • Xiang Hu,
  • Wu Luo

摘要

Myocardial infarction (MI) is an important risk factor of cardiovascular disease (CVD) and its incidence has been on the rise globally. Myocardial ischemia/reperfusion (I/R) injury is frequently detected in the ischemic myocardium. Recent studies have shown that ubiquitination plays an important role in the cardiac pathophysiological processes. Herein, we investigated the role and molecular mechanism of Ovarian tumor deubiquitinase 1 (OTUD1) in I/R induced myocardial injury. It was observed that the myocardial OTUD1 was upregulated in I/R-induced heart tissues and global deletion of OTUD1 significantly ameliorated I/R induced myocardial injury and dysfunction. Similarly, silencing or overexpression OTUD1 affected the hypoxia/reoxygenation (H/R) induced cell apoptosis in cultured cardiomyocytes. Mechanistically, immunoprecipitation-mass spectrometry revealed that OTUD1 directly bound to receptor for activated C-kinase 1 (RACK1) which has been identified as a scaffold protein for multiple kinases including mitogen-activated protein kinase (MAPKs) and Inhibitor of nuclear factor kappa B kinase (IKK). OTUD1 could cleave K63-linked polyubiquitin chains to enhance RACK1 phosphorylation, thus modulating MAPKs and nuclear factor kappa B (NF-κB) signaling. Finally, silencing of RACK1 reverses OTUD1-promoted H/R induced myocardial apoptosis. In conclusion, our findings suggest that OTUD1 promotes I/R-induced heart injury by deubiquitinating RACK1, suggesting that OTUD1 is a potential therapeutic target for myocardial I/R.