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

Cell Reports (Nov 2024)

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

Affiliations

Natalie E. Hong: 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
Alice Chaplin: Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
Lin Di: 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
Anastasia Ravodina: Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
Graham H. Bevan: Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
Huiyun Gao: Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
Courteney Asase: Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
Roopesh Singh Gangwar: 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
Mark J. Cameron: Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
Matthew Mignery: Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
Olga Cherepanova: Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
Aloke V. Finn: Department of Internal Medicine, Cardiovascular Division, University of Maryland School of Medicine, Baltimore, MD, USA; CVPath Institute, Inc., Gaithersburg, MD, USA
Lalitha Nayak: 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
Andrew A. Pieper: 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
Andrei Maiseyeu: Cardiovascular Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Corresponding author

Journal volume & issue: Vol. 43, no. 11
p. 114911

Abstract

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Summary: 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.

CP: Immunology

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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