Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronarysyndromes

Inflammation and oxidative stress contribute to the pathogenesis of many hu man diseases including atherosclerosis. Advanced human atheroma contains hi gh levels of the enzyme myeloperoxidase that produces the pro-oxidant speci es, hypochlorous acid (HOCl). This study documents increased numbers of mye loperoxidase-expressing macrophages in eroded or ruptured plaques causing a cute coronary syndromes. In contrast, macrophages in human fatty streaks co ntain little or no myeloperoxidase. Granulocyte macrophage colony-stimulati ng factor, but not macrophage colony-stimulating factor, selectively regula tes the ability of macrophages to express myeloperoxidase and produce HOCL in vitro. Moreover, myeloperoxidase-positive macrophages in plaques co-loca lized with granulocyte macrophage colony-stimulating factor. Pro-inflammato ry stimuli known to be present in human atherosclerotic plaque, including C D40 ligand, lysophosphatidylcholine, or cholesterol crystals, could induce release of myeloperoxidase from HOCl production by macrophages in vitro. HO Cl-modified proteins accumulated at ruptured or eroded sites of human coron ary atheroma. These results identify granulocyte macrophage colony-stimulat ing factor as an endogenous regulator of macrophage myeloperoxidase express ion in human atherosclerosis and support a particular role for the myeloper oxidase-expressing macrophages in atheroma complication and the acute coron ary syndromes.