MST1 Suppresses Disturbed Flow Induced Atherosclerosis

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Mechanobiology

Background:

• Atherosclerosis develops at arterial sites with disturbed blood flow.
• The role of MST1 (mammalian sterile 20-like kinase 1) in disturbed flow-induced endothelial cell (EC) activation and atherosclerosis is not well understood.

Purpose of the Study:

• To investigate the role of MST1 in endothelial dysfunction and atherosclerosis under disturbed blood flow.
• To elucidate the molecular mechanisms linking MST1, EC activation, and atherogenesis.

Main Methods:

• Utilized EC-specific Mst1-deficient mice on an ApoE background in a carotid artery ligation model.
• Employed mass spectrometry, immunoprecipitation, and dye uptake assays.
• Applied oscillatory shear stress to human and mouse endothelial cells in vitro.

Main Results:

• Endothelial MST1 phosphorylation decreased under oscillatory shear stress.
• MST1 deficiency exacerbated EC activation and atherosclerosis, which was reversed by MST1 re-expression.
• MST1 inhibition reduced Cx43 (connexin 43) phosphorylation and hemichannel activity, contributing to EC dysfunction and atherosclerosis.
• Filamin B facilitates Cx43 translocation to lipid rafts, promoting hemichannel opening.

Conclusions:

• The MST1-Cx43 axis is critical in driving endothelial dysfunction and atherosclerosis under disturbed flow.
• Inhibition of this axis represents a potential therapeutic target for atherosclerosis treatment.