Rab10 plays a protective role in the development of pathological cardiac hypertrophy

Prolonged cardiac hypertrophy is a main risk factor for heart failure (HF). During cardiac hypertrophy remodelling, there is an increase in protein synthesis, as well as the trafficking and localization of proteins to their functional sites. Rab GTPases, which are key regulators of vesicular formation, movement, and fusion, play a crucial role in these processes. In this study, we identified Rab10, a small GTPase belonging to the Rab family, as a novel regulator to inhibit cardiac hypertrophy. Cardiomyocyte hypertrophy was induced by Ang II or pressure overload in primary neonatal rat cardiomyocytes (NRCMs) or mouse model. We found that Rab10 expression was downregulated in NRCMs or murine hearts after hypertrophic stress. Rab10 overexpression attenuated cardiomyocyte hypertrophy, whereas its silencing exacerbated the phenotype, demonstrating its essential antihypertrophic role <i>in vitro</i>. To determine the <i>in vivo</i> role of Rab10 in the heart, we generated cardiac-specific Rab10-overexpressing transgenic mice (TG). When subjected to Ang II infusion or pressure overload, Rab10 TG mice displayed an improved contractile function and attenuated hypertrophic remodelling. In contrast, AAV9-mediated cardiac-specific knockdown of Rab10 significantly aggravated pressure overload-induced cardiomyocyte hypertrophy. Mechanically, Rab10 suppressed the phosphorylation of ERK1/2 and AKT, thereby attenuating the development cardiac hypertrophy. Additionally, we demonstrated that Rab10 was post-transcriptionally downregulated by miR-199a. In summary, our findings revealed a novel role for Rab10 in pathogenic cardiac hypertrophy and suggest that Rab10 may be a potential therapeutic target for cardiac hypertrophic.