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Many data support the concept that atherosclerosis is an inflammatory process. (1,2) The earliest event in atherogenesis appears to be endothelial cell dysfunction. Various noxious insults including hypertension, diabetes, smoking, dyslipidemia, and hyperhomocystinemia can result in endothelial cell dysfunction. After endothelial cell dysfunction, mononuclear cells, such as monocytes (MOs) and T lymphocytes, initially loosely attach to the endothelium, and thereafter adhere firmly to the endothelium and then diapedese into the subendothelial space. The rolling and tethering of leukocytes on the endothelium is orchestrated by adhesion molecules such as selectins (E-selectin, P-selectin), cell adhesion molecules (intercellular adhesion molecule 1, vascular cell adhesion molecule 1), and integrins. Chemotaxis and entry of MOs into the subendothelial space are promoted by MO chemoattractant protein 1, interleukin 8 (IL-8), and a newly reported chemokine, fractalkine. Thereafter, macrophage colony-stimulating factor promotes the differentiation of MOs into macrophages. Macrophages incorporate lipids from oxidized low-density lipoprotein (LDL) via the scavenger receptor pathway (CD36, scavenger receptor A), becoming foam cells, the hallmark of the early fatty streak lesion. After the fatty streak lesion, smooth muscle cells migrate into the intima, proliferate, and form the fibrous cap. It is currently believed that lipid-laden macrophages, during the process of necrosis and apoptosis, release matrix metalloproteinases and other proteases, which cause a rent in the endothelium. Because the lipid-laden macrophage is enriched in tissue factor, this is released from the macrophage and comes in contact with the circulating platelets, resulting in thrombus formation and acute coronary syndromes (unstable angina and myocardial infarction). Thus, the MO-macrophage is a pivotal cell present in all stages of atherogenesis, from the fatty streak lesion to the complicated lesion. Monocytes and macrophages, when appropriately stimulated, can produce many biologically active mediators that can influence virtually all aspects of atherogenesis, such as reactive oxygen species and proinflammatory cytokines such as IL-1 and tumor necrosis factor [alpha] (TNF) and tissue factor. Recent exciting evidence of the pivotal role of MO-macrophages in atherogenesis comes from studies of apolipoprotein E knockout mice (which develop fulminant atherosclerosis). (3-5) In these mice, it has been shown that additional knockout of the gene for CCR2 (the receptor for MO chemotactic protein 1) significantly decreases lesion formation. Also, in osteopetrotic mice, it has been shown that knocking out the gene for macrophage colony-stimulating factor decreased lesion formation in apolipoprotein E knockout mice.