Targeting the ACOD1-itaconate axis stabilizes atherosclerotic plaques

Karl J. Harber, Annette E. Neele, Cindy PAA van Roomen, Marion JJ Gijbels, Linda Beckers, Myrthe den Toom, Bauke V. Schomakers, Daan AF Heister, Lisa Willemsen, Guillermo R. Griffith, Kyra E. de Goede, Xanthe AMH van Dierendonck, Myrthe E. Reiche, Aurélie Poli, Frida L-H Mogensen, Alessandro Michelucci, Sanne GS Verberk, Helga de Vries, Michel van Weeghel, Jan Van den Bossche*Menno PJ de Winther*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

Inflammatory macrophages are key drivers of atherosclerosis that can induce rupture-prone vulnerable plaques. Skewing the plaque macrophage population towards a more protective phenotype and reducing the occurrence of clinical events is thought to be a promising method of treating atherosclerotic patients. In the current study, we investigate the immunomodulatory properties of itaconate, an immunometabolite derived from the TCA cycle intermediate cis-aconitate and synthesised by the enzyme Aconitate Decarboxylase 1 (ACOD1, also known as IRG1), in the context of atherosclerosis. Ldlr−/− atherogenic mice transplanted with Acod1−/− bone marrow displayed a more stable plaque phenotype with smaller necrotic cores and showed increased recruitment of monocytes to the vessel intima. Macrophages from Acod1−/− mice contained more lipids whilst also displaying reduced induction of apoptosis. Using multi-omics approaches, we identify a metabolic shift towards purine metabolism, in addition to an altered glycolytic flux towards production of glycerol for triglyceride synthesis. Overall, our data highlight the potential of therapeutically blocking ACOD1 with the aim of stabilizing atherosclerotic plaques.

Original languageEnglish
Article number103054
JournalRedox Biology
Volume70
DOIs
Publication statusPublished - Apr 2024

Keywords

  • Acod1
  • Atherosclerosis
  • Immunometabolism
  • IRG1
  • Itaconate
  • Macrophage

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