Current Drug Targets - Volume 8, Issue 12, 2007

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.

Altered cellular production of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) is a ubiquitous feature of human disease. Vascular oxidative stress is a unifying area of research in atherosclerosis and aging. While elevated levels of ROS, especially oxygen radicals (O2 -·) and hydrogen peroxide (H2O2), induce cellular apoptosis, low levels play an important role in cell signaling [1,2]. Reactive species from a variety of sources further play an important role in plaque disruption partly through lipid oxidation, low-density lipoprotein oxidation nitration, and signaling [3- 6].

At one time, atherosclerosis was thought to be a simple lipid storage disease. However, it is now recognized as a chronic and progressive inflammation of the arterial wall. Gene deletion experiments in murine models of atherosclerosis that reduce the inflammatory process also reduce disease severity. Identifying the initiators and mediators of that inflammation can provide promising avenues for prevention or therapy. Two prominent risk factors, hyperlipidemia and infectious disease, point to innate immune mechanisms as potential contributors to proatherogenic inflammation. The Tolllike receptors (TLR), proinflammatory sensors of pathogens, are potential links between inflammation, infectious disease and atherosclerosis. There is increasing evidence that TLRs also recognize host-derived ligands and this also connects TLRs to diseases that may not have an etiology that is associated directly with infection. A mechanism for hyperlipidemic initiation of sterile inflammation can be postulated because oxidized lipoproteins or their component oxidized lipids have been identified as TLR ligands. Moreover, infectious agents are correlated with atherosclerosis risk. There are multiple published reports that TLR4 activation is relevant to the inflammation of atherosclerosis in mice and humans. In addition, we have identified a role for TLR2 in atherosclerosis in low density lipoprotein receptor-deficient (LDLr-/-) mice. Proatherogenic TLR2 responses to unknown endogenous or unknown endemic exogenous agonists are mediated by non-bone marrow-derived cells, which can include endothelial cells, adventitial fibroblasts and vascular smooth muscle cells. This is in contrast to the proatherogenic TLR2 response to defined synthetic exogenous agonists, which is mediated at least in part by bone marrow-derived cells, which can include lymphocytes, monocytes/macrophages, NK cells and dendritic cells. Thus, TLR2-mediated cell activation in response to endogenous and exogenous agents is proatherogenic in hyperlipidemic mice.

Atherosclerosis is a chronic inflammatory disease of the arterial wall and an increasing body of evidence suggests that the immune system actively participates in the initiation, progression and persistence of atherosclerosis. Different types of leukocytes such as T and B lymphocytes, natural killer cells (NK) and NKT cells, macrophages, dendritic cells and mast cells have been found within atherosclerosis-prone aortas. The mechanisms of monocyte recruitment have been partially characterized and involve P-selectin, E-selectin, VCAM-1, ICAM-1 and JAM-A. CXCL1, CCL5, CXCL4, CXCL7 and MIF are also implicated in monocyte trafficking into aortas. Recently it has been reported that Ly6Chigh and Ly6Clow monocyte subsets differently use CCL2, CX3CL1 and CCL5 for their homing into atherosclerotic aortas. T and B lymphocytes constitutively migrate into the normal and atherosclerotic aortic wall in an L-selectin-dependent manner. Recent studies suggest an important role of CCL5, CXCL10, CXCL16, CXCR6 and MIF in T cell influx into the atherosclerotic wall. However, there is little information available on the mechanisms of recruitment of other types of the immune cells such as NK, NKT and mast cells. In this review we shall summarize what is known about leukocyte recruitment into the aortic wall during atherosclerosis with a focus on mouse model systems.

Macrophage-derived foam cells play integral roles in all stages of atherosclerosis. These lipid-laden immune cells are present from the earliest discernable fatty-streak lesions to advanced plaques, and are key regulators of the pathologic behavior of plaques. This review summarizes the current understanding of the molecular mechanisms that regulate macrophage cholesterol uptake, foam cell formation, and lipid-driven pro-inflammatory responses that promote atherosclerosis. Specific emphasis will be placed on recent findings from mouse models of atherosclerosis regarding the pathways of macrophage differentiation into foam cells and their implications for developing macrophage-directed therapeutic targets.

Atherosclerosis is a chronic inflammatory disease of the arterial wall initiated by a variety of pro-atherogenic stimuli, such as modified epitopes of phospholipids. Both innate and adaptive immune responses contribute to disease initiation and progression. Here, we review the major cytokines involved in this immuno-inflammatory response, and shown to significantly impact disease initiation and/or progression in murine models. We particularly emphasize the role of the regulatory arm of the immune response in disease modulation, and review the major factors that may be involved in its promotion or alteration.

Nuclear receptors form a large family of ligand-dependent transcription factors that regulate diverse aspects of development and homeostasis. Several of these receptors have been demonstrated to play important roles in controlling biological processes that influence the development and clinical consequences of atherosclerosis. Because nuclear receptors are regulated by small molecules, they are potential targets for anti-atherogenic drugs. In this chapter, we review the use of mouse models to evaluate roles of nuclear receptors and their ligands in the pathogenesis and treatment of atherosclerosis.

Throughout the process of atherosclerosis, lesional macrophages, smooth muscle cells, and possibly endothelial cells undergo programmed cell death, or apoptosis. Under normal physiologic conditions, apoptotic cells are rapidly cleared by neighboring phagocytes, a process called efferocytosis, which prevents secondary cellular necrosis and inflammation. If efferocytosis is not efficient, necrosis, inflammation, and tissue damage ensue. Mouse models of atherosclerosis offer the best opportunity to understand the mechanisms and consequences of lesional cell apoptosis and efferocytosis in atherogenesis and plaque progression. Studies in mice to date have suggested that properly coupled macrophage apoptosis and efferocytosis in early atherosclerosis limits lesion size. The results of other mouse studies suggest that macrophage and smooth muscle cell apoptosis and defective efferocytosis in advanced lesions promotes plaque necrosis. Future insight into these critically important processes will require additional insight into the molecular and cellular mechanisms that lead to lesional cell apoptosis and efferocytosis as well as new mouse models of plaque disruption and thrombosis. Advances in these areas offer great hope for eventual translation into innovative therapeutic strategies to combat atherothrombotic vascular disease.

In this review the modulation of lipoprotein metabolism and atherogenesis by the innate and adaptive immune systems of the mouse is discussed. While recognizing the participation of all components of the immune system in atherogenesis, it is clear that robust atherogenesis may proceed without an adaptive immune response. But even when all components are active, the outcome reflects a balance between pro- and anti-inflammatory reactants and cells. This network of interactions is summarized in this review and is complemented by other reviews in this series. Also noted is the differential response of different vascular beds following manipulation of the components of the adaptive immune system. Further work is required to achieve a fuller understanding of the role of these systems in atherogenesis, especially with the prospect of favorably modulating atherogenesis by the manipulation of the participating immune components as for example in a vaccination approach.

Lipoprotein lipase, hepatic lipase, and endothelial lipase are sn-1 lipases that play important roles in the metabolism of plasma lipoproteins. In vitro and in vivo studies suggest that these lipases exhibit both pro- and antiatherogenic properties, which are dependent primarily on their tissue localization. The following chapter reviews the physiology of these lipases, and the consequences of the loss or gain of function for each lipase in modulating atherosclerosis, with emphasis on murine models.