Article Impact Level: HIGH Data Quality: STRONG Summary of Cell Reports, 43(11), 114911. https://doi.org/10.1016/j.celrep.2024.114911 Dr. Natalie E. Hong et al.
Points
- The study investigates itaconate (ITA) to promote plaque resolution in atherosclerotic cardiovascular disease (ASCVD), addressing the limitations of current therapies that do not fully protect against cardiovascular events.
- Itaconate, produced by macrophages in vulnerable plaques via the IRG1 enzyme, was identified as key to plaque stabilization, especially when paired with a low-cholesterol, low-fat diet (LCLFD).
- Researchers developed an ITA-conjugated lipid nanoparticle (ITA-LNP) to deliver ITA directly to plaque and bone marrow myeloid cells, targeting inflammation at the source.
- ITA-LNP treatment was effective in mouse models, reducing inflammation through epigenetic changes and achieving safe, effective plaque stabilization, even with advanced ASCVD.
- This dual-target approach, addressing plaque inflammation and priming bone marrow progenitor cells, highlights a promising therapeutic strategy for ASCVD patients with residual cardiovascular risk.
Summary
This research paper investigates itaconate (ITA), a tricarboxylic acid cycle intermediate, mediating plaque resolution in atherosclerotic cardiovascular disease (ASCVD). The study highlights the challenges associated with current ASCVD therapies, which fail to protect against cardiovascular events fully. It explores how dietary modifications, particularly a low-cholesterol, low-fat diet (LCLFD), can stabilize plaques and reduce inflammation. The authors found that itaconate, produced by plaque macrophages through the enzyme immunoresponsive gene 1 (IRG1), plays a critical role in plaque resolution. Elevated levels of IRG1 were observed in vulnerable human plaques but not in early or stable plaques. This discovery led to developing an ITA-conjugated lipid nanoparticle (ITA-LNP), which targets plaque and bone marrow myeloid cells, enabling site-specific delivery of ITA.
The study further demonstrates that ITA-LNP treatment effectively recapitulates the beneficial effects of LCLFD-induced plaque resolution in multiple murine atherosclerosis models. ITA-LNPs, which deliver unconjugated ITA intracellularly, accumulate in plaque and bone marrow myeloid cells, eliciting epigenetic changes through H3K27ac deacetylation and reducing inflammation. ITA-LNPs were shown to safely stimulate plaque resolution, even in models with advanced ASCVD, and their use in combination with dietary cessation promoted plaque stabilization. Importantly, this approach was non-toxic and did not elicit adverse effects, demonstrating the potential of ITA-LNPs as a therapeutic agent.
In conclusion, the findings provide new mechanistic insights into diet-driven plaque stabilization and offer a novel treatment strategy for ASCVD that combines targeted plaque resolution with priming of bone marrow progenitor cells. This two-pronged approach targets inflammation at the site of plaques and in myeloid progenitors, offering a promising therapeutic avenue for patients with residual cardiovascular risk despite conventional therapies. The study paves the way for further development of ITA-based treatments to manage atherosclerosis and related cardiovascular complications.
Link to the article: https://www.cell.com/cell-reports/fulltext/S2211-1247(24)01262-2
References Hong, N. E., Chaplin, A., Di, L., Ravodina, A., Bevan, G. H., Gao, H., Asase, C., Gangwar, R. S., Cameron, M. J., Mignery, M., Cherepanova, O., Finn, A. V., Nayak, L., Pieper, A. A., & Maiseyeu, A. (2024). Nanoparticle-based itaconate treatment recapitulates low-cholesterol/low-fat diet-induced atherosclerotic plaque resolution. Cell Reports, 43(11), 114911. https://doi.org/10.1016/j.celrep.2024.114911
