OxLDL induces vascular endothelial cell pyroptosis through miR-125a-5p/TET2 pathway

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Cellular Biology

Background:

• Pyroptosis, a pro-inflammatory cell death, is implicated in atherosclerosis (As) pathogenesis and plaque instability.
• MicroRNAs regulate gene expression post-transcriptionally; miR-125a-5p is elevated in hyperlipidemic-hyperglycemic states and linked to apoptosis, but its role in pyroptosis and As is undefined.

Purpose of the Study:

• To investigate the role of miR-125a-5p in oxidized low-density lipoprotein (oxLDL)-induced pyroptosis of vascular endothelial cells (VECs).
• To elucidate the specific molecular mechanism by which miR-125a-5p influences VEC pyroptosis and its contribution to atherosclerosis.

Main Methods:

• Assessed the effect of miR-125a-5p on TET2 expression in VECs.
• Investigated the downstream consequences of TET2 inhibition, including DNA methylation, mitochondrial function, reactive oxygen species (ROS) production, and NF-κB activation.
• Analyzed inflammasome activation, cytokine release (IL-1β, IL-18), and pyroptosis induction.

Main Results:

• miR-125a-5p was found to inhibit TET2 expression post-transcriptionally in VECs.
• This inhibition led to aberrant DNA methylation, mitochondrial dysfunction, and increased ROS production.
• Activation of NF-κB resulted in inflammasome activation, maturation, and subsequent release of IL-1β and IL-18, culminating in VEC pyroptosis.

Conclusions:

• A novel pathway involving miR-125a-5p and TET2 in VEC pyroptosis was identified, contributing to atherosclerosis development.
• oxLDL-induced VEC pyroptosis mediated by this pathway plays a significant role in vascular pathophysiology and As progression.
• Modulating miR-125a-5p and TET2 levels presents a potential therapeutic target for atherosclerosis.