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
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.
