Editorial [ Murine Atherosclerosis (Part III) Guest Editor: Godfrey S. Getz ]
In this comprehensive collection of reviews of various aspects of atherosclerosis and atherosclerosis biology in mouse models, the first issue dealt with risk factors such as diet, genetics, gender, obesity, diabetes, hypertension, metabolic syndrome and acute inflammation. The second issue was devoted to many putative mechanisms contributing to atherosclerosis. Among the topics reviewed were: the interaction of modified lipoproteins with Toll-like receptors influencing atherosclerosis; the role of oxidative stress in the stimulating atherogenesis; the family of lipases (hepatic, lipoprotein, endothelial) produced by a variety of atherosclerosis relevant cells and capable of influencing lipoprotein homeostasis; the recruitment of blood cells to the vessel wall during atherogenesis; the central role of monocyte derived foam cells in atherosclerosis; the cytokines produced by the variety of cell types among innate and adaptive immune systems that influence atherosclerosis; the role of nuclear receptors in regulating lipoprotein metabolism and macrophage biology; the important effects of apoptosis of cells of the atherosclerotic lesions particularly in influencing the fate of these lesions; and the role of the adaptive immune system in regulating lipoprotein homeostasis and atherogenesis.
In this the third and final issue of the journal devoted to murine atherosclerosis, a variety of additional parameters and potential complications of the atherosclerotic lesion is examined in depth. First an extensive review by Veniant, Beigneux, Bensadoun, Fong and Young is devoted to the influence of lipoprotein size on atherosclerosis susceptibility as determined from genetics studies. Modified lipoproteins that are thought to play an important role in initiating the process of atherosclerosis are also capable of serving as neoantigens, some of which are also seen on the surface of apoptotic cells. The natural antibodies to these neo-antigens are in evidence in atherosclerosis models and may be useful markers of the oxidative aspects of the life history of the atherosclerotic lesion. These antibodies are discussed in detail in the review by Binder and Witztum. The atherosclerotic lesion, despite its complexity and chronicity, is nevertheless a dynamic lesion capable of being reversed or modified particularly by the removal of its lipid content. At least in the mouse, lesion reversibility is surprisingly dynamic. HDL is an agent that affords a major atheroprotective capacity via processes that extend beyond reverse cholesterol transport. These processes are reviewed by Feig, Shamir and Fisher. Based upon the notable atheroprotective and anti-inflammatory properties of HDL, investigators have developed apolipoprotein A-I small peptide mimetics that can be surprisingly effective in reversing atherogenesis and can have other actions on vascular pathobiology in mouse models. This story is reviewed by Navab, Anantharamaiah, Reddy, Van Lenten and Fogelman. In human cardiovascular biology, much attention is paid to the unstable plaque which upon rupture provides a nidus for full thrombus formation and obstruction of vascular channels. One of the limitations of the murine models of atherosclerosis is the difficulty of studying the unstable plaque upon which a thrombus supervenes. However, Rosenfeld, Averill, Bennett and Schwartz have carefully studied the advanced atherosclerotic lesion of apoE deficient mice fed chow. They demonstrate complex lesions with intra-plaque hemorrhage which apparently occurs over ruptured lateral fatty streaks but does not result in occlusive thrombi. They warn against regarding this as a model of the human ruptured plaque which generally involves the fibrous cap and may be accompanied by occlusive thrombi. Despite these observations, a fascinating model of coronary thrombosis and myocardial infarction is seen in the double knockout mouse involving apoE and SRB1 deficiency. Work with this model is carefully reviewed by Braun, Rigotti and Trigatti. Other potential complications of atherosclerosis may involve cartilaginous metaplasia and calcification. These complications have been explored by Hsu, Tintut, and Demer. Several investigators have studied the role of proteins involved in hemostasis on atherogenesis. In the light of the prominence of fibrin deposits and fibrin degradation products in plaques, this topic has been reviewed by Iwaki, Ploplis and Castellino. Surgical intervention with organ transplantation and stenting of atherosclerotic lesions, which involves injury to the plaque surface, may result in blood vessel pathology, either arteriosclerosis or atherosclerosis. This graft atherosclerosis is reviewed by Hu and Xu. Intimal hyperplasia may be a feature of atherosclerosis, but injury induced intimal hyperplasia is probably a separate entity being dominated by proliferating smooth muscle cells. This topic is expertly explored in the review by Hui.
This collection involving 28 separate reviews has extensively explored currently available information on murine atherosclerosis and related pathobiology. Represented in this collection are the many faces of approaches to atherosclerosis from the initial lesion to advanced and complicated plaques, from lipoprotein homeostasis to lipid storage in lesions, from macrophages, T cells and smooth muscle cells to advanced lesions containing extracellular lipid and matrix proteins, from simple lipid lesions to complex and varied lesion phenotypes. All of these changes are influenced by the risk factors, diet, gender, blood pressure and genetics. What emerges from this extensive set of reviews is that we still have a great deal to learn if we are to be able to therapeutically modify the fate of lesions. This looms prominently on the horizon and further studies of these models will undoubtedly reveal many surprises and many opportunities. However one needs to hardly remind oneself of the fact that as useful as murine models may be, they do not accurately mimic what we see in pathologically significant human atherosclerotic plaques. In the initial overview introducing this collection of reviews I pointed out some of the most obvious differences in atherosclerosis relevant factors and phenotypes between mice and humans. The study of human atherosclerosis remains the ultimate arbiter for understanding the application of what we have learned from the mouse models to the therapy of human vascular disease.
I am grateful to Dr Catherine A Reardon for her help with this editorial.
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Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will be devoted to a single timely topic, with series of in-depth reviews, written by leaders in the field, covering a range of current topics on drug targets. These issues will be organized and led by a guest editor who is a recognized expert in the overall topic. As the discovery, identification, characterisation and validation of novel human drug targets for drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.