Scholarlink

<p>Although heart disease arises from different etiologies, treatment remains largely one-size-fits-all, leaving many patients without optimal benefit, which highlights the need for cause-directed therapies. Pathogenic variants in <i>RBM20</i>, a cardiac splicing factor, lead to an aggressive form of dilated cardiomyopathy with high risk of ventricular arrhythmias. We hypothesized that the splicing target calcium/calmodulin-dependent kinase II delta (<i>CAMK2D</i>) is disease causing in RBM20 cardiomyopathy. Here we show that <i>Rbm20/Camk2d</i> double knockout mice are protected from heart failure and sudden cardiac death. In <i>Rbm20</i>-deficient hearts, phosphorylation of CAMK2D targets was increased, indicating that RBM20 loss results not only in mis-splicing of <i>Camk2d</i> transcripts but also in functional activation of CAMK2D signaling. Reexpression of individual CAMK2D splice variants in <i>Rbm20/Camk2d</i> double knockout mice reintroduced cardiac dysfunction, demonstrating that overactivation, rather than mis-splicing, drives disease. Treatment of <i>Rbm20</i>-p.Arg636Gln knockin mice with the ATP-competitive CAMK2 inhibitor hesperadin improved cardiac function. These findings identify CAMK2D overactivation as a central mechanism in RBM20 cardiomyopathy and support CAMK2D inhibition as a promising cause-directed therapy.</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

CAMK2D causes heart failure in mice with RBM20 cardiomyopathy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月4日

查看全文
  • Maarten M. G. van den Hoogenhof,
  • Javier Duran,
  • Thiago Britto-Borges,
  • Vasco Sequeira,
  • Elena Kemmling,
  • Laura Konrad,
  • Friederike Schreiter,
  • David C. Lennermann,
  • Joshua Hartmann,
  • Laura Schraft,
  • Julia Kornienko,
  • Theresa Bock,
  • Marcus Krüger,
  • Christoph Maack,
  • Christoph Dieterich,
  • Lars M. Steinmetz,
  • Matthias Dewenter,
  • Johannes Backs

摘要

Although heart disease arises from different etiologies, treatment remains largely one-size-fits-all, leaving many patients without optimal benefit, which highlights the need for cause-directed therapies. Pathogenic variants in RBM20, a cardiac splicing factor, lead to an aggressive form of dilated cardiomyopathy with high risk of ventricular arrhythmias. We hypothesized that the splicing target calcium/calmodulin-dependent kinase II delta (CAMK2D) is disease causing in RBM20 cardiomyopathy. Here we show that Rbm20/Camk2d double knockout mice are protected from heart failure and sudden cardiac death. In Rbm20-deficient hearts, phosphorylation of CAMK2D targets was increased, indicating that RBM20 loss results not only in mis-splicing of Camk2d transcripts but also in functional activation of CAMK2D signaling. Reexpression of individual CAMK2D splice variants in Rbm20/Camk2d double knockout mice reintroduced cardiac dysfunction, demonstrating that overactivation, rather than mis-splicing, drives disease. Treatment of Rbm20-p.Arg636Gln knockin mice with the ATP-competitive CAMK2 inhibitor hesperadin improved cardiac function. These findings identify CAMK2D overactivation as a central mechanism in RBM20 cardiomyopathy and support CAMK2D inhibition as a promising cause-directed therapy.