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Divergence of acetate uptake in proinflammatory and inflammation-resolving macrophages: implications for imaging atherosclerosis

  • ORIGINAL ARTICLE
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Journal of Nuclear Cardiology Aims and scope

Abstract

Background

Metabolic divergence of macrophages polarized into different phenotypes represents a mechanistically relevant target for non-invasive characterization of atherosclerotic plaques using positron emission tomography (PET). Carbon-11 (11C)-labeled acetate is a clinically available tracer which accumulates in atherosclerotic plaques, but its biological and clinical correlates in atherosclerosis are undefined.

Methods and results

Histological correlates of 14C-acetate uptake were determined in brachiocephalic arteries of western diet-fed apoE−/− mice. The effect of polarizing stimuli on 14C-acetate uptake was determined by proinflammatory (interferon-γ + lipopolysaccharide) vs inflammation-resolving (interleukin-4) stimulation of murine macrophages and human carotid endarterectomy specimens over 2 days. 14C-acetate accumulated in atherosclerotic regions of arteries. CD68-positive monocytes/macrophages vs smooth muscle actin-positive smooth muscle cells were the dominant cells in regions with high vs low 14C-acetate uptake. 14C-acetate uptake progressively decreased in proinflammatory macrophages to 25.9 ± 4.5% of baseline (P < .001). A delayed increase in 14C-acetate uptake was induced in inflammation-resolving macrophages, reaching to 164.1 ± 21.4% (P < .01) of baseline. Consistently, stimulation of endarterectomy specimens with interferon-γ + lipopolysaccharide decreased 14C-acetate uptake to 66.5 ± 14.5%, while interleukin-4 increased 14C-acetate uptake to 151.5 ± 25.8% compared to non-stimulated plaques (P < .05).

Conclusions

Acetate uptake by macrophages diverges upon proinflammatory and inflammation-resolving stimulation, which may be exploited for immunometabolic characterization of atherosclerosis.

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Abbreviations

18F-FDG:

18F-fluorodeoxyglucose

PET:

Positron emission tomography

IL-1β:

Interleukin-1β

IL-4:

Interleukin-4

IFN-γ:

Interferon-γ

LPS:

Lipopolysaccharide

NOS2:

Nitric oxide synthase-2

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Authors and Affiliations

  1. Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA

    Selim Demirdelen MD, Philip Z. Mannes, Ali Mubin Aral MD, Joseph Haddad MD & Sina Tavakoli MD, PhD

  2. Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA

    Steven A. Leers MD

  3. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Delphine Gomez PhD & Sina Tavakoli MD, PhD

  4. Heart, Lung, Blood, and Vascular Medicine Institute, UPMC Department of Medicine, Pittsburgh, PA, USA

    Delphine Gomez PhD & Sina Tavakoli MD, PhD

  5. UPMC Presbyterian Hospital, 200 Lothrop Street, Suite E200, Pittsburgh, PA, 15213, USA

    Sina Tavakoli MD, PhD

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  1. Selim Demirdelen MD
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Correspondence to Sina Tavakoli MD, PhD.

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Funding

This study was supported by grants from National Institutes of Health (NHLBI, K08 HL144911) and Radiological Society of North America (RSD-1820), and a Seed Fund from University of Pittsburgh/UPMC Departments of Radiology and Medicine to S.T; as well as a grant from National Institutes of Health (NHLBI R01 HL146465) to D.G.

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Demirdelen, S., Mannes, P.Z., Aral, A.M. et al. Divergence of acetate uptake in proinflammatory and inflammation-resolving macrophages: implications for imaging atherosclerosis. J. Nucl. Cardiol. 29, 1266–1276 (2022). https://doi.org/10.1007/s12350-020-02479-5

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  • DOI: https://doi.org/10.1007/s12350-020-02479-5

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