Rab26-mediated lysosomal translocation of eEF1A alleviates myocardial hypertrophy and cardiac remodeling

Pathological myocardial hypertrophy and cardiac remodeling are a maladaptive response to stressors such as hypertension and genetic mutations, characterized by cardiomyocyte enlargement, fibrosis, cardiomyocyte apoptosis and impaired cardiac function. Rab26, a small GTPase, plays a crucial role in vesicle trafficking, secretion and apoptosis. However, its role in myocardial hypertrophy and cardiac remodeling remains unclear.

Transverse aortic constriction (TAC) model was employed to induce myocardial hypertrophy and cardiac remodeling, with functional and histological assessments. Cardiac-specific Rab26 overexpression was achieved via AAV9-cTnT-Rab26 delivery, while Rab26 knockout was used for loss-of-function analysis. Molecular mechanisms were explored using protein interaction studies, fluorescence co-localization, and protease inhibition assays.

Our findings indicated a significant downregulation of Rab26 protein expression in the disease model, while its mRNA levels remained unaltered. Notably, cardiac-specific overexpression of Rab26 led to improved cardiac function, decreased cardiac fibrosis, suppressed myocardial hypertrophy and cardiomyocyte apoptosis. Furthermore, the knockout of Rab26 aggravated myocardial hypertrophy and cardiac remodeling. At the mechanistic level, Rab26 facilitates lysosomal translocation and degradation of eEF1A. Additionally, eEF1A silencing eliminated the protective effect of Rab26 on the heart. Comprehensive evaluation revealed the critical role of the Rab26-eEF1A axis in mediating pathological myocardial hypertrophy and cardiac remodeling.

This study suggests that Rab26 prevents cardiac remodeling and dysfunction under pressure overload by promoting the lysosome translocation and degradation of eEF1A. Targeting the Rab26-eEF1A axis thus provides a potential strategy for preventing or reversing myocardial hypertrophy and cardiac remodeling.