Targeting the ACOD1-itaconate axis stabilizes atherosclerotic plaques

Area of Science:

• Immunology
• Metabolic pathways
• Cardiovascular disease

Background:

• Inflammatory macrophages drive atherosclerosis and plaque rupture.
• Modulating macrophage phenotype is a potential therapeutic strategy for atherosclerosis.
• Itaconate, synthesized by Aconitate Decarboxylase 1 (ACOD1), has immunomodulatory properties.

Purpose of the Study:

• To investigate the role of itaconate and ACOD1 in atherosclerosis.
• To explore the potential of targeting ACOD1 for atherosclerotic plaque stabilization.

Main Methods:

• Utilized Ldlr-/- mice transplanted with Acod1-/- bone marrow.
• Employed multi-omics approaches to analyze metabolic and cellular changes.
• Assessed plaque phenotype, necrotic core size, monocyte recruitment, lipid content, and apoptosis.

Main Results:

• Acod1-/- bone marrow transplantation led to more stable plaques with smaller necrotic cores.
• Macrophages from Acod1-/- mice showed increased lipid accumulation and reduced apoptosis.
• Identified metabolic shifts including altered purine metabolism and increased glycerol production for triglyceride synthesis.

Conclusions:

• ACOD1 plays a significant role in regulating macrophage function and plaque stability in atherosclerosis.
• Therapeutically blocking ACOD1 may stabilize atherosclerotic plaques.
• Targeting ACOD1 presents a promising strategy for treating atherosclerosis.