bioRxiv : the preprint server for biology · 2026
GENETIC AND PHARMACOLOGIC ACTIVATION OF BECLIN1 PREVENTS ALDOSTERONE-INDUCED CARDIOVASCULAR DAMAGE.
СтатьяПрепринтНазвание и аннотация: Перевод пока не подготовлен
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Costa Rafael M, Bruder Ariane, Alves Juliano V, Cerqueira Debora M, de Moraes Luis Oliveira, Beling Tyler, Guerrero Sergio, Ho Jaqueline, de Cassia A Tostes Rita, Bruder-Nascimento Thiago
Аннотация
BACKGROUND: Aldosterone promotes endothelial dysfunction and cardiovascular injury through mineralocorticoid receptor (MR) activation. Autophagy is essential for endothelial homeostasis, yet its role in aldosterone-mediated vascular dysfunction remains unclear. We tested whether aldosterone impairs autophagic flux and whether restoring autophagy via Beclin1 (BCN1) activation protects vascular and cardiac function.
METHODS: Endothelial and vascular responses to aldosterone were assessed in wild-type mice, BCN1 gain-of-function mice (Becn1), and mice treated with spermidine or a BCN1-activating TB-peptide. Vascular function, nitric oxide (NO)/reactive oxygen species (ROS) production, autophagy markers, endothelial migration, and cardiac fibrosis were evaluated using wire myography, fluorescence assays, Western blotting, confocal microscopy, migration assays, and histology.
RESULTS: Aldosterone impaired endothelium-dependent relaxation, decreased NO, increased ROS, and disrupted autophagic flux in an MR-dependent manner, indicated by LC3 accumulation and reduced p62 and BCN1 expression. Spermidine restored endothelial function and normalized NO and ROS levels. BCN1 gain-of-function mice were protected from aldosterone-induced endothelial dysfunction and exhibited reduced coronary and myocardial fibrosis. TB-peptide activation of BCN1 enhanced autophagic flux, improved vascular function, decreased cardiac fibrosis, and rescued endothelial migration impaired by aldosterone.
CONCLUSIONS: Aldosterone induces endothelial dysfunction by suppressing autophagic flux through MR activation. Genetic or pharmacologic enhancement of BCN1-dependent autophagy restores endothelial homeostasis and prevents vascular and cardiac injury, identifying autophagy activation as a promising therapeutic approach for cardiovascular diseases associated with mineralocorticoid excess.
METHODS: Endothelial and vascular responses to aldosterone were assessed in wild-type mice, BCN1 gain-of-function mice (Becn1), and mice treated with spermidine or a BCN1-activating TB-peptide. Vascular function, nitric oxide (NO)/reactive oxygen species (ROS) production, autophagy markers, endothelial migration, and cardiac fibrosis were evaluated using wire myography, fluorescence assays, Western blotting, confocal microscopy, migration assays, and histology.
RESULTS: Aldosterone impaired endothelium-dependent relaxation, decreased NO, increased ROS, and disrupted autophagic flux in an MR-dependent manner, indicated by LC3 accumulation and reduced p62 and BCN1 expression. Spermidine restored endothelial function and normalized NO and ROS levels. BCN1 gain-of-function mice were protected from aldosterone-induced endothelial dysfunction and exhibited reduced coronary and myocardial fibrosis. TB-peptide activation of BCN1 enhanced autophagic flux, improved vascular function, decreased cardiac fibrosis, and rescued endothelial migration impaired by aldosterone.
CONCLUSIONS: Aldosterone induces endothelial dysfunction by suppressing autophagic flux through MR activation. Genetic or pharmacologic enhancement of BCN1-dependent autophagy restores endothelial homeostasis and prevents vascular and cardiac injury, identifying autophagy activation as a promising therapeutic approach for cardiovascular diseases associated with mineralocorticoid excess.