Mitochondrial ROS drive foam cell formation via STAT5 signaling in atherosclerosis

Area of Science:

• Cardiovascular Biology
• Cellular Metabolism
• Atherosclerosis Research

Background:

• Macrophage-to-foam cell transition is critical in atherosclerotic plaque development.
• Oxidized low-density lipoprotein (oxLDL) is a key driver of foam cell formation, impacting macrophage function and metabolism.

Purpose of the Study:

• To investigate the role of mitochondrial reactive oxygen species (ROS) in oxLDL-induced macrophage-to-foam cell differentiation.
• To elucidate the molecular mechanisms linking mitochondrial ROS to foam cell formation.

Main Methods:

• Utilized cell culture models and in vivo studies (mouse and human plaques).
• Investigated the impact of oxLDL on macrophage metabolism and STAT5 signaling.
• Assessed the effect of STAT5 inhibition on foam cell differentiation.

Main Results:

• Macrophage oxLDL-derived superoxide promotes mitochondrial metabolic reprogramming, driving foam cell formation.
• Mitochondrial superoxide activates STAT5, reducing tricarboxylic acid cycle activity and enhancing STAT5 target gene accessibility.
• STAT5 signaling is a distinct signature in foam cells, both ex vivo and in vivo.
• STAT5 inhibition prevents the differentiation into mature Trem2hiGpnmbhi foam cells.

Conclusions:

• oxLDL-induced mitochondrial superoxide activates STAT5, creating a feedback loop that drives macrophage-to-foam cell transition.
• Targeting the mitochondrial superoxide-STAT5 axis offers a potential therapeutic strategy for atherosclerosis.