title: Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque.
abstract: Reduced bioavailable nitric oxide (NO) plays a key role in the enhanced leukocyte recruitment reflective of systemic inflammation thought to precede and underlie atherosclerotic plaque formation and instability. Recent evidence demonstrates that inorganic nitrate (NO3-) through sequential chemical reduction in vivo provides a source of NO that exerts beneficial effects upon the cardiovascular system, including reductions in inflammatory responses. We tested whether the antiinflammatory effects of inorganic nitrate might prove useful in ameliorating atherosclerotic disease in Apolipoprotein (Apo)E knockout (KO) mice. We show that dietary nitrate treatment, although having no effect upon total plaque area, caused a reduction in macrophage accumulation and an elevation in smooth muscle accumulation within atherosclerotic plaques of ApoE KO mice, suggesting plaque stabilization. We also show that in nitrate-fed mice there is reduced systemic leukocyte rolling and adherence, circulating neutrophil numbers, neutrophil CD11b expression, and myeloperoxidase activity compared with wild-type littermates. Moreover, we show in both the ApoE KO mice and using an acute model of inflammation that this effect upon neutrophils results in consequent reductions in inflammatory monocyte expression that is associated with elevations of the antiinflammatory cytokine interleukin (IL)-10. In summary, we demonstrate that inorganic nitrate suppresses acute and chronic inflammation by targeting neutrophil recruitment and that this effect, at least in part, results in consequent reductions in the inflammatory status of atheromatous plaque, and suggest that this effect may have clinical utility in the prophylaxis of inflammatory atherosclerotic disease.
authors.affiliation: William Harvey Research Institute, Barts & The London Medical School, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors.forename: Rayomand S
authors.initials: RS
authors.lastname: Khambata
authors.affiliation: William Harvey Research Institute, Barts & The London Medical School, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors.forename: Suborno M
authors.initials: SM
authors.lastname: Ghosh
authors.affiliation: William Harvey Research Institute, Barts & The London Medical School, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors.forename: Krishnaraj S
authors.initials: KS
authors.lastname: Rathod
authors.affiliation: William Harvey Research Institute, Barts & The London Medical School, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors.forename: Tharssana
authors.initials: T
authors.lastname: Thevathasan
authors.affiliation: William Harvey Research Institute, Barts & The London Medical School, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors.forename: Federica
authors.initials: F
authors.lastname: Filomena
authors.affiliation: William Harvey Research Institute, Barts & The London Medical School, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: William Harvey Research Institute, Barts & The London Medical School, Queen Mary University of London, London EC1M 6BQ, United Kingdom a.ahluwalia@qmul.ac.uk.
authors.forename: Amrita
authors.initials: A
authors.lastname: Ahluwalia
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000097:blood / Q000494:pharmacology*; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D016207:Cytokines / Q000097:blood / Q000235:genetics; D004032:Diet; D059305:Diet, High-Fat; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D008297:Male; D008643:Mesentery / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D009566:Nitrates / Q000097:blood / Q000494:pharmacology*; D009573:Nitrites / Q000097:blood; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D016207:Cytokines; D009566:Nitrates; D009573:Nitrites
keywords: atherosclerosis; diet; inflammation; nitrate; nitric oxide