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Published on: July 27, 2022
CAMK2D causes heart failure in mice with RBM20 cardiomyopathy
Maarten M G van den Hoogenhof1,2,3,4, Javier Duran5,6,7,8, Thiago Britto-Borges7,9
1Heidelberg University, Medical Faculty Heidelberg, Institute of Experimental Cardiology, Heidelberg, Germany. maarten.hoogenhof@cardioscience.uni-heidelberg.de.
Insights
RBM20 gene variants cause dilated cardiomyopathy by overactivating CAMK2D signaling. Inhibiting CAMK2D offers a targeted therapy for this aggressive heart disease, improving cardiac function and survival.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genetic Heart Disease
Background:
- Heart disease treatments are often generalized, necessitating cause-directed therapies.
- Pathogenic variants in the RBM20 gene cause aggressive dilated cardiomyopathy and increase arrhythmia risk.
Purpose of the Study:
- To investigate the role of calcium/calmodulin-dependent kinase II delta (CAMK2D) as a disease-causing factor in RBM20 cardiomyopathy.
- To explore CAMK2D inhibition as a potential cause-directed therapy.
Main Methods:
- Generated and analyzed Rbm20/Camk2d double knockout mice.
- Assessed cardiac function and signaling pathways in mouse models.
- Evaluated the therapeutic effect of the CAMK2 inhibitor hesperadin in RBM20 cardiomyopathy models.
Main Results:
- Rbm20/Camk2d double knockout mice were protected from heart failure and sudden cardiac death.
- RBM20 deficiency led to increased phosphorylation of CAMK2D targets, indicating functional CAMK2D overactivation.
- Reintroducing CAMK2D splice variants caused cardiac dysfunction, confirming overactivation drives disease.
- Hesperadin treatment improved cardiac function in RBM20 cardiomyopathy mice.
Conclusions:
- CAMK2D overactivation is a central mechanism in RBM20-related cardiomyopathy.
- Targeted inhibition of CAMK2D represents a promising therapeutic strategy for RBM20 cardiomyopathy.
Abstract:
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.
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