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

Natalie E Hong; Alice Chaplin; Lin Di; Anastasia Ravodina; Graham H Bevan; Huiyun Gao; Courteney Asase; Roopesh Singh Gangwar; Mark J Cameron; Matthew Mignery; Olga Cherepanova; Aloke V Finn; Lalitha Nayak; Andrew A Pieper; Andrei Maiseyeu

doi:10.1016/j.celrep.2024.114911

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

Cell Rep. 2024 Nov 26;43(11):114911. doi: 10.1016/j.celrep.2024.114911. Epub 2024 Oct 28.

Authors

Affiliations

¹ Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
² Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
³ Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Division of Allergy and Immunology, Department of Medicine, University of Virginia, Charlottesville, VA, USA.
⁴ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
⁵ Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
⁶ Department of Internal Medicine, Cardiovascular Division, University of Maryland School of Medicine, Baltimore, MD, USA; CVPath Institute, Inc., Gaithersburg, MD, USA.
⁷ Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Department of Hematology & Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
⁸ Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA; Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes VA Medical Center, Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA; Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA.
⁹ Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH, USA. Electronic address: [email protected].

Abstract

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.

Keywords: ApoE(−/−) mice; CP: Immunology; TCA cycle; atherosclerosis; cholesterol; itaconate; nanoparticle; plaque resolution.

MeSH terms

Animals
Atherosclerosis / drug therapy
Atherosclerosis / pathology
Diet, Fat-Restricted
Humans
Hydro-Lyases
Inflammation / drug therapy
Inflammation / pathology
Macrophages / drug effects
Macrophages / metabolism
Male
Mice
Mice, Inbred C57BL*
Nanoparticles* / chemistry
Nanoparticles* / therapeutic use
Plaque, Atherosclerotic* / drug therapy
Plaque, Atherosclerotic* / pathology
Succinates* / pharmacology
Succinates* / therapeutic use

Substances

itaconic acid
Succinates
Acod1 protein, mouse
Hydro-Lyases