Scholarlink

<p>Diabetic cardiomyopathy (DCM) is a medical condition characterized by cardiac remodeling and dysfunction in individuals with diabetes mellitus. Sarcoplasmic reticulum (SR) and mitochondrial Ca<sup>2+</sup> overload in cardiomyocytes have been recognized as biological hallmarks in DCM; however, the specific factors underlying these abnormalities remain largely unknown. In this study, we aimed to investigate the role of a cardiac-specific long noncoding RNA, <i>D830005E20Rik</i> (<i>Trdn-as</i>), in DCM. Our results revealed the remarkably upregulation of <i>Trdn-as</i> in the hearts of the DCM mice and cardiomyocytes treated with high glucose (HG). Knocking down <i>Trdn-as</i> in cardiac tissues significantly improved cardiac dysfunction and remodeling in the DCM mice. Conversely, <i>Trdn-as</i> overexpression resulted in cardiac damage resembling that observed in the DCM mice. At the cellular level, <i>Trdn-as</i> induced Ca<sup>2+</sup> overload in the SR and mitochondria, leading to mitochondrial dysfunction. RNA-seq and bioinformatics analyses identified calsequestrin 2 (Casq2), a primary calcium-binding protein in the junctional SR, as a potential target of <i>Trdn-as</i>. Further investigations revealed that <i>Trdn-as</i> facilitated the recruitment of METTL14 to the <i>Casq2</i> mRNA, thereby enhancing the m<sup>6</sup>A modification of <i>Casq2</i>. This modification increased the stability of <i>Casq2</i> mRNA and subsequently led to increased protein expression. When <i>Casq2</i> was knocked down, the promoting effects of <i>Trdn-as</i> on Ca<sup>2+</sup> overload and mitochondrial damage were mitigated. These findings provide valuable insights into the pathogenesis of DCM and suggest <i>Trdn-as</i> as a potential therapeutic target for this condition.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Cardiomyocyte-specific long noncoding RNA Trdn-as induces mitochondrial calcium overload by promoting the m6A modification of calsequestrin 2 in diabetic cardiomyopathy

  • 期刊论文

  • 发表日期：

    2025年1月17日

查看全文
  • Xiaohan Li,
  • Ling Liu,
  • Han Lou,
  • Xinxin Dong,
  • Shengxin Hao,
  • Zeqi Sun,
  • Zijia Dou,
  • Huimin Li,
  • Wenjie Zhao,
  • Xiuxiu Sun,
  • Xin Liu,
  • Yong Zhang,
  • Baofeng Yang

摘要

Diabetic cardiomyopathy (DCM) is a medical condition characterized by cardiac remodeling and dysfunction in individuals with diabetes mellitus. Sarcoplasmic reticulum (SR) and mitochondrial Ca2+ overload in cardiomyocytes have been recognized as biological hallmarks in DCM; however, the specific factors underlying these abnormalities remain largely unknown. In this study, we aimed to investigate the role of a cardiac-specific long noncoding RNA, D830005E20Rik (Trdn-as), in DCM. Our results revealed the remarkably upregulation of Trdn-as in the hearts of the DCM mice and cardiomyocytes treated with high glucose (HG). Knocking down Trdn-as in cardiac tissues significantly improved cardiac dysfunction and remodeling in the DCM mice. Conversely, Trdn-as overexpression resulted in cardiac damage resembling that observed in the DCM mice. At the cellular level, Trdn-as induced Ca2+ overload in the SR and mitochondria, leading to mitochondrial dysfunction. RNA-seq and bioinformatics analyses identified calsequestrin 2 (Casq2), a primary calcium-binding protein in the junctional SR, as a potential target of Trdn-as. Further investigations revealed that Trdn-as facilitated the recruitment of METTL14 to the Casq2 mRNA, thereby enhancing the m6A modification of Casq2. This modification increased the stability of Casq2 mRNA and subsequently led to increased protein expression. When Casq2 was knocked down, the promoting effects of Trdn-as on Ca2+ overload and mitochondrial damage were mitigated. These findings provide valuable insights into the pathogenesis of DCM and suggest Trdn-as as a potential therapeutic target for this condition.