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.