ELABELA restores cardiac function, reverses hypertrophy in hereditary hypertrophic cardiomyopathy mouse models

Hereditary hypertrophic cardiomyopathy (HCM) is a prevalent genetic heart disease leading to heart failure and sudden cardiac death. Current therapeutic options are limited; for instance, the myosin inhibitor mavacamten faces constraints due to safety concerns and restricted applicability. ELABELA (ELA), an endogenous ligand for the apelin receptor (APJ), is crucial in cardiovascular regulation, yet its specific role in HCM pathophysiology has remained largely undefined. This study aimed to elucidate ELA's involvement and explore the therapeutic potential of restoring its signaling pathway.

Researchers examined ELABELA and APJ expression in myocardial tissues from HCM patients and in two distinct sarcomere mutation-driven mouse models of HCM. The therapeutic effects of ELABELA were assessed through AAV9-mediated overexpression and chronic administration of mature ELABELA peptide. Cardiac function and remodeling were rigorously evaluated using echocardiography and histological analyses. Cellular and molecular mechanisms were further investigated via cardiomyocyte calcium imaging, contractility assays, comprehensive transcriptomic analysis, and targeted pharmacological interventions.

ELABELA expression was significantly reduced, while APJ expression was notably increased, in both human and murine HCM hearts. Restoration of ELABELA signaling markedly improved cardiac function, alleviated pathological hypertrophy and fibrosis, and enhanced diastolic performance across both HCM mouse models. In vitro, ELABELA successfully normalized cardiomyocyte hypertrophy, corrected abnormal Ca2+ transients, and reduced hypercontractility. Mechanistically, ELABELA suppressed Ca2+-dependent activation of the calcineurin-NFAT and MAPK signaling pathways in an APJ-dependent manner. Importantly, sustained ELABELA overexpression for up to 12 months maintained its therapeutic efficacy without any evidence of receptor desensitization. This long-term stability suggests a durable therapeutic effect. The findings highlight a conserved deficiency of ELABELA in hereditary HCM and its critical role in cardiac health.

Restoring ELABELA-APJ signaling reversed cardiac dysfunction and pathological remodeling by normalizing Ca2+ handling and inhibiting hypertrophic pathways.