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Updated: Jun 23, 2026
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Therapeutic potential of ELABELA in alleviating hereditary hypertrophic cardiomyopathy
1MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China; Department of Cardiothoracic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214122, China.
Insights
Hereditary hypertrophic cardiomyopathy (HCM) is linked to reduced ELABELA (ELA) levels. Restoring ELA-APJ signaling improves cardiac function and reduces pathological remodeling in HCM, offering a new therapeutic strategy.
Area of Science:
- Cardiovascular Biology
- Genetic Cardiology
- Molecular Medicine
Background:
- Hereditary hypertrophic cardiomyopathy (HCM) is a prevalent genetic heart condition linked to heart failure and sudden cardiac death.
- Current treatments for HCM are limited, with emerging therapies like mavacamten facing safety and applicability challenges.
- ELABELA (ELA), an apelin receptor (APJ) ligand, is crucial for cardiovascular regulation, but its role in HCM is not well understood.
Purpose of the Study:
- To investigate the role of ELA in hereditary HCM.
- To evaluate the therapeutic potential of restoring ELA signaling in HCM.
Main Methods:
- Examined ELA and APJ expression in human and mouse HCM tissues.
- Utilized AAV9-mediated ELA overexpression and peptide administration in mouse models.
- Assessed cardiac function, remodeling, and molecular mechanisms via echocardiography, histology, calcium imaging, and transcriptomics.
Main Results:
- Found significantly reduced ELA and increased APJ expression in HCM hearts.
- Demonstrated that restoring ELA signaling improved cardiac function, reduced hypertrophy and fibrosis, and enhanced diastolic performance in HCM models.
- Showed ELA normalized cardiomyocyte function in vitro by suppressing calcineurin-NFAT and MAPK pathways via APJ.
Conclusions:
- ELA deficiency is a consistent finding in hereditary HCM.
- Restoring ELA-APJ signaling effectively reverses cardiac dysfunction and pathological remodeling in HCM.
- ELA represents a promising therapeutic target for modifying HCM progression.
Introduction:
Hereditary hypertrophic cardiomyopathy (HCM) is a common genetic heart disease associated with heart failure and sudden cardiac death. Current therapies are limited, and the myosin inhibitor mavacamten is constrained by safety concerns and restricted applicability. ELABELA (ELA), an endogenous ligand of the apelin receptor (APJ), plays an important role in cardiovascular regulation, but its involvement in HCM remains unclear.
Objectives:
This study aimed to determine the role of ELA in hereditary HCM and to assess the therapeutic potential of restoring ELA signaling.
Methods:
ELA and APJ expression were examined in myocardial tissues from HCM patients and in two sarcomere mutation-driven mouse models of HCM. The effects of ELA were evaluated using AAV9-mediated overexpression and chronic administration of mature ELA peptide. Cardiac function and remodeling were assessed by echocardiography and histology. Cellular and molecular mechanisms were investigated using cardiomyocyte calcium imaging, contractility assays, transcriptomic analysis, and pharmacological interventions.
Results:
ELA expression was significantly reduced, whereas APJ expression was increased, in human and murine HCM hearts. Restoration of ELA signaling markedly improved cardiac function, alleviated pathological hypertrophy and fibrosis, and improved diastolic performance in both HCM models. In vitro, ELA normalized cardiomyocyte hypertrophy, corrected abnormal calcium (Ca2⁺) transients, and reduced hypercontractility. Mechanistically, ELA suppressed Ca2⁺-dependent activation of the calcineurin-NFAT and MAPK signaling pathways in an APJ-dependent manner. Sustained ELA overexpression for up to 12 months maintained therapeutic efficacy without evidence of receptor desensitization.
Conclusions:
ELA deficiency is a conserved feature of hereditary HCM. Restoring ELA-APJ signaling reverses cardiac dysfunction and pathological remodeling by normalizing Ca2+ handling and inhibiting hypertrophic signaling pathways, identifying ELA as a promising disease-modifying therapeutic target for HCM.
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