Novel Circular RNA circEZH2 Shows Promise in Preventing Endothelial Cell Aging and Atherosclerosis
Researchers identified a circular RNA called circEZH2 that is reduced in aging blood vessels and atherosclerotic plaques, and demonstrated that restoring it delays cellular senescence and suppresses atherosclerosis progression in mice. The study reveals that circEZH2 works by stabilizing a protein called ZNF326 through a molecular scaffolding mechanism. This finding suggests circEZH2 could be developed as a therapeutic target for age-related heart disease.
A new study published on bioRxiv describes the discovery of circEZH2, a circular RNA modified by m6A methylation, which protects endothelial cells (the inner lining of blood vessels) from aging and prevents atherosclerosis development. Using microarray profiling and molecular screening, researchers found that circEZH2 levels decrease in aged aortic tissue and advanced atherosclerotic plaques. When circEZH2 was overexpressed in endothelial cells, it delayed cellular senescence, reduced markers of aging (p53/p21), and enhanced the cells' ability to form new blood vessels. Mechanistically, circEZH2 acts as a molecular scaffold that stabilizes the protein ZNF326 by promoting its deubiquitination through the enzyme USP37. Importantly, knocking down ZNF326 reversed the protective effects of circEZH2, confirming this protein is essential to the pathway. The findings suggest that restoring circEZH2 levels could represent a novel therapeutic strategy for treating age-related atherosclerosis.
Limitations & open questions
The study is a preprint that has not yet undergone peer review. The authors do not discuss potential off-target effects of circEZH2 manipulation, the translational timeline for moving from mouse models to human therapies, or how circEZH2-based interventions might interact with existing atherosclerosis treatments. Additionally, the study focuses on circEZH2 overexpression but does not explore whether pharmacological stabilization of endogenous circEZH2 (without genetic modification) is feasible.
What different sources said
- bioRxivCenter
M6A-modified circEZH2 Protects Endothelial Cells from Senescence and Suppresses Atherosclerosis by Stabilizing ZNF326
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