Homocysteine‑induced oxidative stress through TLR4/NF‑κB/DNMT1‑mediated LOX‑1 DNA methylation in endothelial cells

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Cellular Pathology

Background:

• Atherosclerosis (AS) is a complex, progressive disease initiated by endothelial injury.
• Elevated homocysteine (Hcy) is implicated in endothelial dysfunction and oxidative stress, but mechanisms are unclear.
• Lectin-like oxidized-low density lipoprotein receptor-1 (LOX-1) plays a role in endothelial response to injury.

Purpose of the Study:

• To investigate if Hcy induces endothelial cell (EC) injury via LOX-1 DNA methylation.
• To elucidate the role of the toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB/DNA methyltransferase (DNMT)1 pathway in Hcy-induced EC damage.
• To explore the association between Hcy, oxidative stress, and LOX-1 expression in ECs.

Main Methods:

• Endothelial cells were treated with varying concentrations of Hcy.
• Oxidative stress markers (superoxide dismutase, malondialdehyde, hydrogen peroxide) were measured.
• The effect of pyrrolidine dithiocarbamate (PDTC) on NF-κB and DNMT1 was assessed.

Main Results:

• Hcy promoted TLR4 expression, leading to EC injury.
• Hcy induced LOX-1 DNA hypomethylation, increasing LOX-1 expression.
• Hcy-induced EC injury involved methylation and trans-sulfuration metabolism of LOX-1 through the TLR4/NF-κB/DNMT1 pathway.

Conclusions:

• Hcy injures endothelial cells by modulating LOX-1 DNA methylation via the TLR4/NF-κB/DNMT1 signaling cascade.
• This Hcy-induced endothelial injury facilitates lipid accumulation, promoting atherosclerosis progression.
• Understanding these mechanisms offers potential therapeutic targets for atherosclerosis.