J Adv Res. 2026 Jun 21:S2090-1232(26)00509-6. doi: 10.1016/j.jare.2026.06.027. Online ahead of print.
ABSTRACT
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.
PMID:42324018 | DOI:10.1016/j.jare.2026.06.027