Selim Demirdelen1, Philip Z Mannes1, Ali Mubin Aral1, Joseph Haddad1, Steven A Leers2, Delphine Gomez3,4, Sina Tavakoli5,6,7,8. 1. Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA. 2. Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. 3. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. 4. Heart, Lung, Blood, and Vascular Medicine Institute, UPMC Department of Medicine, Pittsburgh, PA, USA. 5. Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA. sit23@pitt.edu. 6. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. sit23@pitt.edu. 7. Heart, Lung, Blood, and Vascular Medicine Institute, UPMC Department of Medicine, Pittsburgh, PA, USA. sit23@pitt.edu. 8. UPMC Presbyterian Hospital, 200 Lothrop Street, Suite E200, Pittsburgh, PA, 15213, USA. sit23@pitt.edu.
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.
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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