Christine H J Kim1, James B Mitchell2, Christina A Bursill3, Anastasia L Sowers4, Angela Thetford5, John A Cook6, David M van Reyk7, Michael J Davies8. 1. Free Radical Group, Heart Research Institute, 7 Eliza Street, Newtown, NSW 2042, Australia; Faculty of Medicine, University of Sydney, NSW 2006, Australia. Electronic address: christinehjkim@gmail.com. 2. National Cancer Institute, Radiation Biology Branch, Center for Cancer Research, Building 10, Room B3-B69, Bethesda, MD 20892, USA. Electronic address: jbm@helix.nih.gov. 3. Faculty of Medicine, University of Sydney, NSW 2006, Australia; Immunobiology Group, Heart Research Institute, 7 Eliza Street, Newtown, NSW 2042, Australia. Electronic address: bursillc@hri.org.au. 4. National Cancer Institute, Radiation Biology Branch, Center for Cancer Research, Building 10, Room B3-B69, Bethesda, MD 20892, USA. Electronic address: stasia@mail.nih.gov. 5. National Cancer Institute, Radiation Biology Branch, Center for Cancer Research, Building 10, Room B3-B69, Bethesda, MD 20892, USA. Electronic address: thetforda@mail.nih.gov. 6. National Cancer Institute, Radiation Biology Branch, Center for Cancer Research, Building 10, Room B3-B69, Bethesda, MD 20892, USA. Electronic address: cook@helix.nih.gov. 7. Faculty of Science, University of Technology Sydney, PO Box 123, Broadway, NSW 2007, Australia. Electronic address: david.vanreyk@uts.edu.au. 8. Free Radical Group, Heart Research Institute, 7 Eliza Street, Newtown, NSW 2042, Australia; Faculty of Medicine, University of Sydney, NSW 2006, Australia; Department of Biomedical Sciences, Building 4.5, Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. Electronic address: davies@sund.ku.dk.
Abstract
OBJECTIVE: The nitroxide compound TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl radical) has been shown to prevent obesity-induced changes in adipokines in cell and animal systems. In this study we investigated whether supplementation with TEMPOL inhibits inflammation and atherosclerosis in apoE-/- mice fed a high fat diet (HFD). METHODS: ApoE-/- mice were fed for 12 weeks on standard chow diet or a high-fat diet. Half the mice were supplemented with 10 mg/g TEMPOL in their food. Plasma samples were analysed for triglycerides, cholesterol, low- and high-density lipoprotein cholesterol, inflammatory cytokines and markers (interleukin-6, IL-6; monocyte-chemotactic protein, MCP-1; myeloperoxidase, MPO; serum amyloid A, SAA; adiponectin; leptin). Plaques in the aortic sinus were analysed for area, and content of collagen, lipid, macrophages and smooth muscle cells. RESULTS: High fat feeding resulted in marked increases in body mass and plasma lipid levels. Dietary TEMPOL decreased both parameters. In the high-fat-fed mice significant elevations in plasma lipid levels and the inflammatory markers IL-6, MCP-1, MPO, SAA were detected, along with an increase in leptin and a decrease in adiponectin. TEMPOL supplementation reversed these effects. When compared to HFD-fed mice, TEMPOL supplementation increased plaque collagen content, decreased lipid content and increased macrophage numbers. CONCLUSIONS: These data indicate that in a well-established model of obesity-associated hyperlipidaemia and atherosclerosis, TEMPOL had a significant impact on body mass, atherosclerosis, hyperlipidaemia and inflammation. TEMPOL may therefore be of value in suppressing obesity, metabolic disorders and increasing atherosclerotic plaque stability.
OBJECTIVE: The nitroxide compound TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl radical) has been shown to prevent obesity-induced changes in adipokines in cell and animal systems. In this study we investigated whether supplementation with TEMPOL inhibits inflammation and atherosclerosis in apoE-/- mice fed a high fat diet (HFD). METHODS:ApoE-/- mice were fed for 12 weeks on standard chow diet or a high-fat diet. Half the mice were supplemented with 10 mg/g TEMPOL in their food. Plasma samples were analysed for triglycerides, cholesterol, low- and high-density lipoprotein cholesterol, inflammatory cytokines and markers (interleukin-6, IL-6; monocyte-chemotactic protein, MCP-1; myeloperoxidase, MPO; serum amyloid A, SAA; adiponectin; leptin). Plaques in the aortic sinus were analysed for area, and content of collagen, lipid, macrophages and smooth muscle cells. RESULTS: High fat feeding resulted in marked increases in body mass and plasma lipid levels. Dietary TEMPOL decreased both parameters. In the high-fat-fed mice significant elevations in plasma lipid levels and the inflammatory markers IL-6, MCP-1, MPO, SAA were detected, along with an increase in leptin and a decrease in adiponectin. TEMPOL supplementation reversed these effects. When compared to HFD-fed mice, TEMPOL supplementation increased plaque collagen content, decreased lipid content and increased macrophage numbers. CONCLUSIONS: These data indicate that in a well-established model of obesity-associated hyperlipidaemia and atherosclerosis, TEMPOL had a significant impact on body mass, atherosclerosis, hyperlipidaemia and inflammation. TEMPOL may therefore be of value in suppressing obesity, metabolic disorders and increasing atherosclerotic plaque stability.
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