Mechanosensitive snoRNA-like circular RNA sno-circCNOT1 drives endothelial dysfunction and atherosclerosis.

Area of Science:

• Molecular Biology
• Cardiovascular Research
• RNA Biology

Background:

• Hemodynamic shear stress is crucial in atherosclerosis, but molecular links to endothelial activation are unclear.
• Circular RNAs (circRNAs) are involved in endothelial mechanotransduction.
• The role of mechanosensitive small nucleolar RNA (snoRNA)-like circRNAs in atherosclerosis is unknown.

Purpose of the Study:

• To investigate the role of snoRNA-like circRNAs, specifically sno-circCNOT1, in endothelial function and atherosclerosis.
• To elucidate the molecular mechanisms by which sno-circCNOT1 regulates endothelial pyroptosis and inflammation under shear stress.
• To identify potential therapeutic targets for atherosclerosis based on the discovered pathway.

Main Methods:

• Characterization of sno-circCNOT1 using RNA sequencing, RNA interference, immunofluorescence, and co-immunoprecipitation.
• Functional studies in endothelial cells and ApoE-/- mice to assess pyroptosis and atherogenesis.
• Mechanistic investigations including RNA pull-down, mass spectrometry, and gain/loss-of-function assays.

Main Results:

• Identified sno-circCNOT1, upregulated by pro-atherogenic stimuli and downregulated by laminar shear stress.
• sno-circCNOT1 mediates shear stress-dependent endothelial pyroptosis and inflammation, aggravating atherosclerosis in mice.
• Discovered the LMNA/METTL14/NLRP3 axis regulated by sno-circCNOT1, promoting endothelial inflammation.

Conclusions:

• sno-circCNOT1 is a mechanosensitive snoRNA-like circRNA promoting endothelial pyroptosis and atherogenesis via the LMNA/METTL14/NLRP3 pathway.
• The METTL14-N component of this axis presents a potential protein-based therapeutic target for atherosclerosis.
• This regulatory pathway is a druggable target for treating atherosclerosis.