Downregulation of MYBL1 in endothelial cells contributes to atherosclerosis by repressing PLEKHM1-inducing autophagy

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Cellular Signaling

Background:

• MYBL1 is a transcriptional activator with known roles in cell signaling.
• The specific role of MYBL1 in the pathogenesis of atherosclerosis remains unelucidated.
• Atherosclerosis is a complex inflammatory disease of the arteries.

Purpose of the Study:

• To investigate the role and underlying mechanisms of MYBL1 in atherosclerosis.
• To determine the effect of MYBL1 on endothelial cell function in the context of atherosclerosis.

Main Methods:

• Bioinformatic analysis of public microarray datasets (GSE28829, GSE43292, GSE41571) for MYBL1 expression.
• Validation of MYBL1 expression in atherosclerotic plaques using qRT-PCR, Western blot, and immunohistochemistry.
• In vitro studies using human umbilical vein endothelial cells (HUVECs) involving MYBL1 knockdown/overexpression, Transwell assays, CCK-8 assays, RNA-seq, immunofluorescence, flow cytometry, ChIP, CO-IP, and luciferase reporter assays to explore mechanisms including autophagy and lipid accumulation.

Main Results:

• MYBL1 expression was significantly downregulated in human atherosclerotic plaque tissues compared to normal vessels.
• Silencing MYBL1 in HUVECs impaired cell migration and proliferation, while MYBL1 overexpression enhanced these functions.
• MYBL1 knockdown led to abnormal autophagy in HUVECs by inhibiting PLEKHM1-mediated autophagosome-lysosome fusion, exacerbating atherosclerosis, and also increased lipid accumulation in HUVECs treated with oxLDL.

Conclusions:

• MYBL1 plays a protective role in atherosclerosis by promoting endothelial cell function and regulating autophagy.
• MYBL1 exerts its protective effects partly by inhibiting lipid accumulation and enhancing autophagosome-lysosome fusion via PLEKHM1.
• Targeting MYBL1 or the PLEKHM1-mediated autophagy pathway presents a potential therapeutic strategy for atherosclerosis.