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

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Cellular Signaling

Background:

• Prolonged cardiac hypertrophy is a significant risk factor for heart failure (HF).
• Rab GTPases regulate protein trafficking crucial for cellular remodeling during hypertrophy.
• The specific role of Rab10 in cardiac hypertrophy remained largely unexplored.

Purpose of the Study:

• To identify novel regulators of cardiac hypertrophy.
• To investigate the role of Rab10 in the development and progression of cardiac hypertrophy.
• To explore the therapeutic potential of Rab10 in cardiac hypertrophy.

Main Methods:

• Induction of cardiomyocyte hypertrophy using Ang II or pressure overload in neonatal rat cardiomyocytes (NRCMs) and a mouse model.
• Assessment of Rab10 expression levels under hypertrophic conditions.
• Manipulation of Rab10 levels (overexpression and knockdown) in vitro and in vivo (cardiac-specific transgenic mice and AAV9-mediated knockdown).
• Evaluation of cardiac function and hypertrophic remodeling.
• Mechanistic studies involving ERK1/2 and AKT phosphorylation and miR-199a regulation.

Main Results:

• Rab10 expression was significantly downregulated in response to hypertrophic stimuli.
• Rab10 overexpression attenuated cardiac hypertrophy in vitro and in vivo, improving cardiac function.
• Rab10 knockdown exacerbated pressure overload-induced cardiac hypertrophy.
• Rab10 suppressed ERK1/2 and AKT phosphorylation, key pathways in hypertrophy.
• Rab10 was post-transcriptionally downregulated by miR-199a.

Conclusions:

• Rab10 acts as a novel endogenous inhibitor of cardiac hypertrophy.
• Rab10 deficiency exacerbates cardiac hypertrophy, highlighting its protective role.
• Rab10 represents a potential therapeutic target for treating pathogenic cardiac hypertrophy and preventing heart failure.