Nanoparticle-based itaconate treatment recapitulates low-cholesterol/low-fat diet-induced atherosclerotic plaque resolution

• Published in: Cell reports (Cambridge) Vol. 43; no. 11; p. 114911
• Main Authors: Hong, Natalie E., Chaplin, Alice, Di, Lin, Ravodina, Anastasia, Bevan, Graham H., Gao, Huiyun, Asase, Courteney, Gangwar, Roopesh Singh, Cameron, Mark J., Mignery, Matthew, Cherepanova, Olga, Finn, Aloke V., Nayak, Lalitha, Pieper, Andrew A., Maiseyeu, Andrei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2024; Elsevier
• Subjects: ApoE−/− mice; atherosclerosis; cholesterol; CP: Immunology; itaconate; nanoparticle; plaque resolution; TCA cycle; atherosclerosis; CP: Immunology; itaconate; plaque resolution; TCA cycle; cholesterol; nanoparticle; ApoE−/− mice; ApoE(−/−) mice
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114911

Current pharmacologic treatments for atherosclerosis do not completely protect patients; additional protection can be achieved by dietary modifications, such as a low-cholesterol/low-fat diet (LCLFD), that mediate plaque stabilization and inflammation reduction. However, this lifestyle modification can be challenging for patients. Unfortunately, incomplete understanding of the underlying mechanisms has thwarted efforts to mimic the protective effects of a LCLFD. Here, we report that the tricarboxylic acid cycle intermediate itaconate (ITA), produced by plaque macrophages, is key to diet-induced plaque resolution. ITA is produced by immunoresponsive gene 1 (IRG1), which we observe is highly elevated in myeloid cells of vulnerable plaques and absent from early or stable plaques in mice and humans. We additionally report development of an ITA-conjugated lipid nanoparticle that accumulates in plaque and bone marrow myeloid cells, epigenetically reduces inflammation via H3K27ac deacetylation, and reproduces the therapeutic effects of LCLFD-induced plaque resolution in multiple atherosclerosis models. [Display omitted] •Itaconate (ITA) mediates diet-driven plaque resolution in ASCVD•ITA-bearing lipid nanoparticles (ITA-LNPs) target plaque and bone marrow myeloid cells•ITA-LNP treatment recapitulates LCLFD-induced atherosclerotic plaque resolution•ITA-LNP treatment downregulates inflammatory genes via H3K27ac deacetylation Hong et al. report that the tricarboxylic acid cycle metabolite itaconate (ITA) mediates low-cholesterol/low-fat-diet-induced atherosclerotic plaque resolution. Additionally, administration of nanoparticle-based ITA therapy induces plaque resolution in several models of atherosclerosis via multiple mechanisms, including epigenetic immunomodulation via H3K27ac deacetylation.