Highlights
- •Low shear stress inhibits endothelial mitophagy.
- •Caveolin-1 and miR-7-5p play an important role in the process of low shear stress inhibiting endothelial mitophagy.
- •Endothelial mitophagy associates with oxidative stress reaction and endothelial dysfunction.
Abstract
Background and aims
Mitophagy plays a crucial role in mitochondrial homeostasis and is closely associated
with endothelial function. However, the mechanism underlying low blood flow shear
stress (SS), detrimental cellular stress, regulating endothelial mitophagy is unclear.
This study aimed to investigate whether low SS inhibits endothelial mitophagy via caveolin-1 (Cav-1)/miR-7-5p/Sequestosome 1 (SQSTM1) signaling pathway.
Methods
Low SS in vivo modeling was induced using a perivascular SS modifier implanted in the carotid artery
of mice. In vitro modeling, low and physiological SS (4 and 15 dyn/cm2, respectively) were exerted on human aortic endothelial cells using a parallel plate
chamber system.
Results
Compared with physiological SS, low SS significantly inhibited endothelial mitophagy
shown by down-regulation of SQSTM1, PINK1, Parkin, and LC 3II expressions. Deficient
mitophagy deteriorated mitochondrial dynamics shown by up-regulation of Mfn1 and Fis1
expression and led to decreases in mitochondrial membrane potential. Cav-1 plays a
bridging role in the process of low SS inhibiting mitophagy. The up-regulated miR-7-5p
expression induced by low SS was suppressed after Cav-1 was silenced. The results
of dual-luciferase reporter assays showed that miR-7-5p targeted inhibiting the SQSTM1 gene. Oxidative stress reaction shown by the elevation of reactive oxygen species
and O2●— and endothelial dysfunction by the decrease in nitric oxide and the increase in macrophage
chemoattractant protein-1 were associated with the low SS inhibiting endothelial mitophagy
process.
Conclusions
Cav-1/miR-7-5p/SQSTM1 signaling pathway was the mechanism underlying low SS inhibiting
endothelial mitophagy that involves mitochondrial homeostasis impairment and endothelial
dysfunction.
Graphical abstract
Graphical Abstract
Keywords
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Article Info
Publication History
Published online: July 30, 2022
Accepted:
July 21,
2022
Received in revised form:
June 20,
2022
Received:
March 13,
2022
Identification
Copyright
© 2022 Published by Elsevier B.V.
