Genetics of atherosclerosis in murine models

The pathology of atherosclerotic lesions that develop in mouse models of atherosclerosis, such as those lacking apolipoprotein E or lacking the low density lipoprotein receptor, is very similar to that seen in human patients. Consequently, genetic approaches to studying atherosclerosis in these mouse models have produced a wealth of information relevant to the genetic factors and pathways that modify the early stages of atherosclerosis in humans. Despite these advances, the later stages of atherosclerosis in humans, including spontaneous plaque rupture and hemorrhage, have not been observed reliably in current mouse models. Increasing sophistication and use of genetic manipulations, however, has produced significant advances in modeling these processes. The use of genetic tools to examine the physiology, pathology, and cell biology of atherosclerosis will enhance elucidation of the pathogenesis of the disease and lead to the development of novel therapeutic strategies.     

Myocardial infarction following atherosclerosis in murine models

The most widely used mouse models for atherosclerosis are LDL receptor knockout (KO) mice and apolipoprotein E (apoE) KO mice fed standard chow diets or lipid-supplemented diets. Unfortunately, these do not usually exhibit myocardial infarction or other features of human cardiovascular disease such as occlusive coronary artery disease, cardiac dysfunction and/or reduced lifespan. Surgical models of myocardial infarction are successfully used for drug testing analyses during acute ischemia, but do not allow investigation of underlying mechanisms related to atherosclerotic coronary artery disease. Recently, experts in the pharmaceutical industry as well as some at the US Food and Drug Administration have identified inadequate animal models as being one of the major hurdles in drug discovery and development. There is an important need for additional well-characterized, genetically manipulable, small animal models that mimic many features of human coronary heart disease (CHD), which would provide investigators in academia and in the pharmaceutical industry with a better system to unravel the pathophysiology of atherosclerotic CHD and to evaluate pre-clinical drug candidates. Here we will review recently developed mouse models of occlusive CHD, focusing on mice lacking expression of the HDL receptor, SR-BI in the context of reduced expression of apoE.     

Lipases as modulators of atherosclerosis in murine models

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 anti-atherogenic 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.     

Cytokines as regulators of atherosclerosis in murine models

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.     

Gender as a regulator of atherosclerosis in murine models

The risk of development and progression of atherosclerosis is different between males and females. Premenopausal women have a lower risk of developing atherosclerosis and cardiovascular disease than men. However, after the onset of menopause the protection associated with gender is lost and the risk of women developing atherosclerosis gradually approaches that of men. In an effort to treat the elevated risk of cardiovascular disease in postmenopausal women, hormone replacement therapy has been used. However, the results of the randomized trials of the Women's Health Initiative indicated that hormone replacement therapy may not be cardioprotective. The use of mouse models have aided in the understanding of atherosclerosis for many years. These models along with the gender effects attributed to sex hormones are being used to generate a more complete understanding of the development of atherosclerosis. Mice lacking one or both of the genes for estrogen receptors have highlighted the role of estrogen in atherosclerosis. In addition to estrogen, the effects of testosterone have been researched in many animal models and several mechanisms incorporating its role in cholesterol homeostasis have emerged. Our understanding of the pathways involved in gender effects on cardiovascular disease is incomplete, however, a plethora of animal models offer the opportunity to dissect the molecular mechanisms involved.     

Metabolic syndrome as a modifier of atherosclerosis in murine models

The Metabolic Syndrome is a common metabolic disease associated with an increased risk for atherosclerotic cardiovascular disease and mortality. In contrast to "traditional" risk factors for atherosclerosis, such as low-density lipoprotein cholesterol, the Metabolic Syndrome represents a network of interacting risk factors stemming from the metabolic complexity of this disease. For this reason, dissection of the cellular and molecular pathways underlying atherosclerosis-susceptibility in the Metabolic Syndrome has been difficult. To facilitate this endeavor, several murine models have been recently developed. Despite their imperfect representation of the Metabolic Syndrome and atherosclerosis in humans, these models have provided important mechanistic insights and revealed novel molecular pathways. Furthermore, murine models are invaluable for the evaluation of therapeutic approaches and will no doubt facilitate the genetic dissection of atherosclerosis-susceptibility in the Metabolic Syndrome.     

Natural antibodies in murine atherosclerosis

Natural antibodies are preformed antibodies that are present even in naive germ-free mice in the absence of any exogenous antigenic exposure. Consistent with their specificities for microbial antigens, natural antibodies play an important non-redundant role in the first line defense against bacterial and viral infections. On the other hand natural antibodies have also been shown to have specificities for self antigens, and therefore have been proposed to provide important homeostatic "house-keeping" functions. Many of the recognized self-antigens may in fact be stress-induced self-antigens, such as oxidation-specific epitopes that accumulate during atherogenesis as well as in many other inflammatory settings, and natural antibodies could protect from the impact of the pathological accumulation of these self-antigens. In this review we will discuss the specific example of the prototypic natural antibody T15/EO6, which is increased in atherosclerotic mice and mediates atheroprotection, and discuss the potential role of natural antibodies in atherogenesis in general.     

Macrophage-derived foam cells in atherosclerosis: lessons from murine models and implications for therapy

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.     

The hemostasis system in murine atherosclerosis

Atherosclerosis is a self-sustaining inflammatory fibroproliferative disease that progresses in discrete stages and involves a number of cell types and effector molecules. The potential importance of the coagulation, anticoagulation, and fibrinolytic systems in atherosclerosis is based on the observation that fibrin deposits and fibrin degradation products are resident in atherosclerotic plaques. A number of investigations have been conducted to probe the relationships between components of the hemostasis system and atherosclerosis; and these types of studies proliferated after the availability of mice genetically manipulated to emphasize the impact of genes of interest. In order to summarize recent progress in this area, this review is focused on mice lacking individual hemostasis genes and their contributions to steps of the atherosclerotic process.     

Overview of murine atherosclerosis series

This volume recognizes the critical and central role of the mouse in experimental atherosclerosis pathology. Atherosclerosis is a complex and chronic inflammation in which multiple modulating factors may play a role. Its chronicity and complexity make it very difficult to study the detailed mechanisms of atherogenesis in unregulated human populations. The search for atherogenic mechanisms requires a model in which these mechanisms simulate those inferred in humans, and in which controlled experiments may be conducted in a reasonable timeframe and at manageable expense. The mouse recommends itself as a small animal model with a short life span in which atherosclerosis similar in character to human atherosclerosis may be induced under controlled conditions. With the development of genetic models of atherosclerosis the mouse has become a very accessible model, especially with the very large genetic data base about this species in relation to human biology that has become available.     

The immune system and murine atherosclerosis

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.     

Intimal hyperplasia in murine models

The most commonly used procedures to induce arterial injury in mice are carotid artery ligation with cessation of blood flow and mechanically-induced denudation of endothelium in the carotid or the femoral arteries. Both procedures result in neointimal hyperplasia after two to three weeks. A survey of various inbred strains of mice shows that strain-specific differences in susceptibility to injury-induced neointimal hyperplasia are different than those for susceptibility to diet-induced atherosclerosis, with strains identified as susceptible to both neointimal hyperplasia and atherosclerosis, resistant to both, susceptible to atherosclerosis but resistant to neointimal hyperplasia, or resistant to atherosclerosis but susceptible to neointimal hyperplasia. Inflammatory cells such as T and B lymphocytes, which are contributory to atherosclerosis, are protective against injury-induced neointimal hyperplasia. In contrast, the infiltration of monocytes into the site of injury and their differentiation to macrophages favor neointimal hyperplasia similar to their pathogenic role in atherosclerosis. The regulatory role of lymphocytes and macrophages in neointimal hyperplasia is related to the production of cytokines such as interferon-gamma and tumor necrosis factor-alpha, respectively. Interestingly, inducible nitric oxide synthase (iNOS) activity appears to inhibit neointimal hyperplasia in the endothelial denudation model but contributes to neointimal hyperplasia when arterial injury is induced by periadventitial cuff placement. The difference appears to be due to the time required for endothelial recovery and the participation of inflammatory cells. Thus, although arterial injury-induced neointimal hyperplasia results in similar vascular occlusion as progressive atherosclerosis, the pathology and mechanism of the two disease processes are quite different.     

不同时期家兔动脉粥样硬化模型的比较

目的 从动脉粥样硬化（AS）发生进展的不同时期,对家兔模型进行比较和研究。方法 新西兰白兔30只,随机分为5组,包括对照组和模型组,模型组又分为AS 4周组、AS 8周组、AS 12周组和AS 16周组,每组6只。对照组给予普通饲料喂养,模型组给予高脂饲料喂养。分别于实验0、4、8、12、16周给各组动物称质量,耳缘静脉取血,测定血清胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白（LDL）和高密度脂蛋白（HGL）含量;通过石蜡切片HE染色及冰冻切片油红O染色对胸主动脉进行病理形态学观察。结果 实验4周时,模型组家兔体质量增加值明显高于对照组,而在实验8、12、16周时,二者比较没有明显差异。血脂测定显示,模型组TC和LDL水平增加幅度较大,TG和HDL水平增加幅度较小,但是与对照组比较差异有显著性（P<0.05、0.01）。组织病理学检查结果显示,实验4周时,模型组家兔在主动脉内皮下可见少量脂质沉积,油红O染色呈红色;实验8周和12周时,处于动脉粥样硬化脂纹期的不同阶段,病灶处内皮下可见大量的泡沫细胞聚集;实验16周时,处于动脉粥样硬化纤维斑块期,病灶表层可见覆盖以纤维帽,纤维帽下有数量不等的泡沫细胞,平滑肌细胞、炎细胞等。结论 家兔单纯给予高脂饲料喂饲4～16周,可造成不同病理分期的动脉粥样硬化模型。     

Apoptosis and efferocytosis in mouse models 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.     

Oxidative stress as a regulator of murine atherosclerosis

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].     

Sexual dimorphism in rodent models of hypertension and atherosclerosis

Approximately one third of all deaths are attributed to cardiovascular disease (CVD), making it the biggest killer worldwide. Despite a number of therapeutic options available, the burden of CVD morbidity continues to grow indicating the need for continued research to address this unmet need. In this respect, investigation of the mechanisms underlying the protection that premenopausal females enjoy from cardiovascular-related disease and mortality is of interest. In this review, we discuss the essential role that rodent animal models play in enabling this field of research. In particular, we focus our discussion on models of hypertension and atherosclerosis.     

普伐他汀对鼠动脉粥样硬化及炎症因子的影响

目的 研究普伐他汀对鼠动脉粥样硬化形成过程及炎症因子的影响.方法 取40只大鼠制作动脉粥样硬化模型,随机分为正常饮食组（A）、对照组（B）、普伐他汀（C,10mg＆#183;kg-1＆#183;d-1）、普伐他汀（D,20mg＆#183;kg-1＆#183;d-1）各10只.B、C、D组定期腹腔注射维生素D破坏内皮细胞,喂养3个月,抽血检测hs-CRP,IL-6,并解剖大鼠制作病理切片,最后处死所有大鼠.结果 B组病理切片显示内膜明显增厚,管壁弥漫性隆起,内皮下含大量泡沫细胞,中膜平滑肌细胞增生.而A组内膜光滑,内皮下未见泡沫细胞,中膜平滑肌排列整齐有序,未见增生改变,C、D组内膜增生情况较B组轻,较A组重,且C组较D组增生明显.炎症因子hs-CRP,IL-6在B、C、D、A中的检测水平依次下降,B组较A组、B组较C组、B组较D组、C组较D组差异均有统计学意义（P＜0.05）.结论 普伐他汀有降低炎症因子,抑制动脉粥样硬化形成的作用.