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BETs that cover the spread from acquired to heritable heart failure
Michael Alexanian1, Saptarsi M Haldar1,2,3
1Gladstone Institutes, San Francisco, California, USA.
The Journal of Clinical Investigation
|August 11, 2020
Summary
Dilated cardiomyopathy (DCM) can be caused by genetic mutations, such as in LMNA. Researchers found that targeting bromodomain and extraterminal (BET) proteins offers a potential treatment for this heart failure syndrome.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Heart failure (HF) with reduced contractile function is a major cause of mortality.
- Dilated cardiomyopathy (DCM) is a subset of HF characterized by a poorly contracting heart without common stressors.
- Germline variants in cardiomyocyte genes, including LMNA, are identified causes of heritable DCM.
Purpose of the Study:
- To investigate the pathogenesis of heritable DCM caused by LMNA mutations.
- To identify potential therapeutic targets for LMNA-associated DCM.
Main Methods:
- Generation of a mouse model with cardiomyocyte-specific deletion of Lmna.
- Analysis of cardiac function and molecular mechanisms in the mouse model.
- Investigation of bromodomain and extraterminal (BET) protein involvement.
Main Results:
- Cardiomyocyte-specific deletion of Lmna recapitulates DCM phenotypes in mice.
- BET protein activation was identified as a key mechanism in disease pathogenesis.
- Pharmacological inhibition of BET proteins showed potential therapeutic effects.
Conclusions:
- LMNA mutations lead to DCM through epigenetic dysregulation involving BET proteins.
- BET protein activation represents a druggable target for treating heritable DCM.
- This study provides a novel therapeutic strategy for a subset of heart failure patients.
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