Laminar flow inhibits the Hippo/YAP pathway via autophagy and SIRT1-mediated deacetylation against atherosclerosis

Area of Science:

• Vascular Biology
• Cellular Mechanotransduction
• Molecular Cardiology

Background:

• Atherosclerosis is a vascular disease influenced by blood flow patterns.
• The Hippo/YAP pathway regulates inflammatory gene expression in response to mechanical cues.
• The precise mechanisms by which blood flow patterns modulate YAP activity are not fully understood.

Purpose of the Study:

• To investigate the role of autophagy and SIRT1 in mediating the effects of shear stress on YAP activity in endothelial cells.
• To elucidate the signaling pathways linking laminar and disturbed blood flow to YAP regulation and inflammatory responses.

Main Methods:

• Examined autophagic markers (BECLIN 1, LC3II/LC3I) under different flow conditions.
• Utilized chemical inhibitors and genetic manipulation to modulate autophagy and SIRT1.
• Assessed YAP nuclear import, transcriptional activity, and acetylation.
• Investigated gene expression of pro-inflammatory markers.
• Studied effects in mouse models of atherosclerosis.

Main Results:

• Laminar flow increased autophagy markers and SIRT1 expression.
• Autophagy blockade under laminar flow prevented YAP degradation.
• Autophagy induction under disturbed flow inhibited YAP nuclear import and activation.
• SIRT1 deacetylated YAP, attenuating its activation and pro-inflammatory gene expression.
• Rapamycin-induced autophagy in mice enhanced SIRT1 and repressed YAP.

Conclusions:

• Endothelial autophagy and SIRT1 induced by laminar flow inhibit Hippo/YAP signaling.
• This mechanism plays a protective role against atherosclerotic plaque formation.
• Targeting autophagy and SIRT1 may offer therapeutic strategies for atherosclerosis.