Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque
Significance Reduced bioavailable nitric oxide generated within the vascular wall is a key pathogenic mechanism involved in the formation and rupture of an atheromatous plaque, the latter leading to myocardial infarction or stroke. We show that inorganic nitrate supplementation through delivery of nitric oxide reduces systemic leukocyte rolling and adherence, circulating neutrophil numbers, and monocyte activation through direct repression of neutrophil activation and up-regulation of interleukin-10–dependent antiinflammatory pathways in athero-prone mice. These antiinflammatory effects of inorganic nitrate result in reduced macrophage content of atherosclerotic plaques coupled with an elevation of smooth muscle content, resulting in a stable plaque phenotype. Our data suggest that inorganic nitrate supplementation has antiinflammatory effects, which may have clinical utility in the prophylaxis of atheroma development. 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 (NO 3 − ) 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.
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