Editorial [Hot Topic: Murine Atherosclerosis (Part II) (Guest Editor: Godfrey S. Getz)]

Atherosclerosis is a complex chronic inflammatory response to lipoprotein dysfunction, especially in experimental animals. It involves the modification and retention of lipoproteins within the intima. This elicits an activation of the endothelium resulting in upregulation of the expression of adhesion molecules and chemokines, both of which promote the recruitment of monocytes. Once in the intima, these monocytes are transformed to macrophages. The macrophages are multi-functional cells that not only take up a variety of modified lipoproteins to become foam cells, but also exert complex pro- and anti-inflammatory influences, mediated mostly by the secretion of cytokines but also by cell-cell interactions. Also recruited to the intima are a variety of subsets of T cells that are capable of influencing macrophage biology and are themselves influenced by the macrophages. Many of the monocytes/macrophages undergo apoptosis, which if not removed by efficient phagocytosis creates a body of secondary necrotic cells responsible for the necrotic core of advanced atherosclerotic lesions. The crosstalk between the major cell participants in atherogenesis sets up a very complex set of local interactions. The complexity of these interactions is reflected in the very large number of manipulations that are capable of exerting substantial effects on experimental atherosclerosis. Each of these stages of atherogenesis is explored in the reviews that follow. In the first issue devoted to murine atherogenesis, we focused on the variety of risk factors that might impact on mouse atherosclerotic lesion development. These included diet, genetics, gender, hypertension, obesity, diabetes, acute inflammatory markers, and metabolic syndrome. This second issue is devoted to the exploration of mechanistic influences related to the process of atherogenesis. Thus the relationship between oxidative stress and atherogenesis is reviewed by Berliner and colleagues. Lipoproteins when modified may activate toll-like receptors. Their involvement in murine atherogenesis is reviewed by Tobias and Curtiss. Brown and Rader review the biology of the three lipase family members, lipoprotein lipase, hepatic lipase and endothelial lipase. They influence atherosclerosis by hydrolyzing lipoprotein lipids or by tethering lipoproteins to cell surface proteoglycans and receptors The recruitment of the cellular components, monocytes and T cells in particular, to the evolving atherosclerotic plaque is discussed in detail by Galkina and Ley. The uptake of modified lipoproteins and storage of cholesterol esters is the subject of a review by Moore and Webb, who also discuss cholesterol efflux from these cells. The role of cytokines produced by the cellular participants in the plaque is discussed by Mallat and Tedgui. They note the participation of both pro-and anti-inflammatory cytokines and also discuss in detail the involvement of regulatory T cells. The phenotype of the macrophage of the lesion is possibly influenced by the generation of intracellular sets of the ligands that influence gene transcription. Their targets are the nuclear hormone receptors, which are discussed extensively by Li and Glass in their review. The number of macrophage foam cells is the result the relative rates of recruitment, egress and cell death. The latter is reviewed in detail by Tabas. The local immune network that constitutes the atherosclerotic lesion is reviewed by Getz, VanderLaan and Reardon. In the third issue that will complete the series, various complications of atherosclerosis and potential therapeutic approaches will bring this extensive series on murine atherosclerosis to an end.