GENETIC AND PHARMACOLOGIC ACTIVATION OF BECLIN1 PREVENTS ALDOSTERONE-INDUCED CARDIOVASCULAR DAMAGE

Area of Science:

• Cardiovascular Biology
• Cellular Biology
• Molecular Medicine

Background:

• Aldosterone promotes cardiovascular injury via mineralocorticoid receptor (MR) activation.
• Autophagy is crucial for endothelial homeostasis, but its role in aldosterone-induced vascular dysfunction is unknown.
• This study investigates aldosterone's effect on autophagic flux and the protective potential of Beclin1 (BCN1) activation.

Purpose of the Study:

• To determine if aldosterone impairs autophagic flux.
• To investigate if restoring autophagy via Beclin1 (BCN1) activation protects vascular and cardiac function.
• To explore therapeutic strategies for cardiovascular diseases linked to mineralocorticoid excess.

Main Methods:

• Assessed endothelial and vascular responses in wild-type, BCN1 gain-of-function mice, and mice treated with spermidine or a BCN1-activating TB-peptide.
• Evaluated vascular function, nitric oxide (NO)/reactive oxygen species (ROS) production, autophagy markers, endothelial migration, and cardiac fibrosis.
• Utilized wire myography, fluorescence assays, Western blotting, confocal microscopy, migration assays, and histology.

Main Results:

• Aldosterone impaired endothelium-dependent relaxation, decreased NO, increased ROS, and disrupted autophagic flux in an MR-dependent manner.
• Spermidine and BCN1 gain-of-function restored endothelial function and normalized NO/ROS levels.
• BCN1 activation protected against aldosterone-induced endothelial dysfunction, reduced cardiac fibrosis, and rescued endothelial migration.

Conclusions:

• Aldosterone induces endothelial dysfunction by suppressing autophagic flux via MR activation.
• Enhancing BCN1-dependent autophagy restores endothelial homeostasis and prevents cardiovascular injury.
• Autophagy activation is a potential therapeutic target for mineralocorticoid excess-related cardiovascular diseases.