12/15-lipoxygenase mediates disturbed flow-induced endothelial dysfunction and atherosclerosis

Area of Science:

• Vascular biology
• Molecular mechanisms of atherosclerosis
• Enzyme function in cardiovascular disease

Background:

• Disturbed blood flow is a key factor in endothelial dysfunction and atherosclerosis.
• 12/15-lipoxygenase (12/15-LOX) is a potential therapeutic target for atherosclerosis.
• The role of 12/15-LOX in disturbed flow-induced atherosclerosis is not well understood.

Purpose of the Study:

• To investigate the relationship between 12/15-LOX and disturbed flow-induced atherosclerosis.
• To elucidate the molecular mechanisms by which disturbed flow affects 12/15-LOX expression and function.
• To evaluate the therapeutic potential of targeting the 12/15-LOX pathway.

Main Methods:

• Comparing 12/15-LOX expression in endothelial cells under steady vs. disturbed flow in vivo and in vitro.
• Utilizing ALOX15 knockout mice, shRNA knockdown, and specific inhibitors to assess 12/15-LOX function.
• Employing a partial carotid ligation mouse model to study atherosclerosis development.

Main Results:

• 12/15-LOX expression is significantly upregulated in endothelial cells at disturbed flow sites.
• 12/15-LOX promotes endothelial dysfunction and atherosclerosis development under disturbed flow.
• Disturbed flow activates 12/15-LOX via SREBP2, leading to increased pro-inflammatory 15s-HETE production.
• Inhibition of 12/15-LOX attenuated atherosclerosis in disturbed flow regions.

Conclusions:

• Disturbed flow upregulates 12/15-LOX through SREBP2, exacerbating endothelial dysfunction and atherosclerosis.
• Targeting the SREBP2-12/15-LOX pathway offers a promising therapeutic strategy for disturbed flow-induced atherosclerosis.