Current Drug Targets

ISSN: 1389-4501

Current Drug Targets
Volume 8, Number 11, November 2007

Contents

Maurine Models of Atherosclerosis
Guest Editor: Godfrey S. Getz


Overview of Murine Atherosclerosis Series Pp. 1144-1149
G.S. Getz
[Abstract]


Diet Effects on Atherosclerosis in Mice Pp. 1150-1160
R.E. Temel and L.L. Rudel
[Abstract]


Genetics of Atherosclerosis in Murine Models Pp. 1161-1171
M. Altenburg, J. Homeister, H. Doherty and N. Maeda
[Abstract]


Gender as a Regulator of Atherosclerosis in Murine Models Pp. 1172-1180
C.M. Thomas and E.J. Smart
[Abstract]


Atherosclerosis and Arterial Blood Pressure in Mice Pp. 1181-1189
H. Lu, L.A. Cassis and A. Daugherty
[Abstract]


Adipose Tissue and the Vessel Wall Pp. 1190-1195
T. Mazzone
[Abstract]


Effects of Diabetes on Murine Lipoproteins and Vascular Disease Pp. 1196-1202
H.M. Dansky and I.J. Goldberg
[Abstract]


The Influence of Acute Phase Proteins on Murine Atherosclerosis Pp. 1203-1214
G.D. Wool and C.A. Reardon
[Abstract]


Metabolic Syndrome as a Modifier of Atherosclerosis in Murine Models Pp. 1215-1220
M. Péterfy, R.C. Davis and A.J. Lusis
[Abstract]




Abstracts

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Overview of Murine Atherosclerosis Series
G.S. Getz

This volume recognizes the critical and central role of the mouse in experimental atherosclerosis pathology. Atherosclerosis is a complex and chronic inflammation [1] 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 [1].


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Diet Effects on Atherosclerosis in Mice
R.E. Temel and L.L. Rudel

The development of atherosclerosis in mice can be dramatically affected by the composition of the diet. The nutrients that seem to have the greatest impact on the atherosclerotic process in not only mice but also humans are fat and cholesterol. For this reason, many murine diets have been created that contain different levels of cholesterol and numerous types of fat. Typically, these diets cause the accumulation of atherogenic, apoB-containing lipoproteins in plasma and depending upon the severity of the hypercholesterolemia stimulate the formation of aortic atherosclerosis that often progresses from fatty streak lesions to advanced, fibrous plaques. In this review, we compare the abilities of diets enriched with various amounts of cholesterol and different types of saturated, monounsaturated, and polyunsaturated fats to promote atherosclerosis in an assortment of mouse models. In addition, we make recommendations concerning the utilization of these diets to promote atherosclerotic lesion formation in mice.


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Genetics of Atherosclerosis in Murine Models
M. Altenburg, J. Homeister, H. Doherty and N. Maeda

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.


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Gender as a Regulator of Atherosclerosis in Murine Models
C.M. Thomas and E.J. Smart

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.


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Atherosclerosis and Arterial Blood Pressure in Mice
H. Lu, L.A. Cassis and A. Daugherty

Increased blood pressure is a consistent risk factor for the development of atherosclerotic diseases in humans, although the basis for this relationship is unknown. Genetically engineered mice are now commonly used to study mechanisms of atherosclerosis. More recently, blood pressure can be reliably measured in conscious mice using either tail cuff or telemetric techniques. Thus, mouse models permit the investigation of the complex interactions of blood pressure and atherogenesis. Most mouse models exhibiting hypertension have increased atherosclerotic lesion size, although there have been exceptions to these findings. Also, there are several reports that have used methods to decrease blood pressure and demonstrated reduced atherosclerosis. In contrast, there are many studies in which atherosclerosis has been altered without changes in blood pressure, and conversely, studies in which blood pressure changes did not alter atherosclerosis. Studies that have specifically defined the role of elevated systolic blood pressure on the development of atherosclerosis have uniformly demonstrated that pressure per se is not responsible for changes in lesion development. Thus, while increased systolic blood pressure is frequently associated with atherosclerosis, the stimulus for the hypertension appears to be the major determinant of atherogenesis rather than pressure per se. A consistent theme in the literature has been that perturbations of the renin angiotensin system display the strongest correlations between blood pressure and atherosclerosis.


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Adipose Tissue and the Vessel Wall
T. Mazzone

The prevalence of obesity is rising dramatically in developed and developing countries. Obesity contributes to increased mortality from numerous causes, but the most important of these is cardiovascular death. The relationship between obesity and atherogenesis is multifactorial, including alterations in the composition and level of lipoproteins, changes in blood pressure, and changes in circulating coagulation and inflammatory factors. Mouse models can be useful for dissecting selected aspects of this complex relationship. One area in which these models can be of particular value is in investigating the effect of secretory products of adipose tissue on the vessel wall. Adipocytes and adipose tissue secrete numerous factors and their level of expression is altered in obese states. Adipose tissue and adipocytes produce adiponectin, resistin, leptin, and apolipoproteins (serum amyloid A and apoE); all of which can directly impact vessel wall homeostasis. Mouse models utilizing deletion or overexpression of many of these factors have demonstrated an important impact of these on vessel wall homeostasis. Subsequent to the development of obesity, factors secreted from adipose tissue have also been shown to have direct effect on liver production of systemic inflammatory factors. Mouse models have validated the importance of angiotensin II, TNFα, and MCP-1 for impacting vessel wall health in obese states. In summary, excess adipose tissue produces myriad changes in organismal homeostasis with potential impact on the vessel wall. The power of mouse genetics permits targeted mechanistic investigation for understanding how obesity accelerates atherosclerosis in a complex in vivo milieu.


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Effects of Diabetes on Murine Lipoproteins and Vascular Disease
H.M. Dansky and I.J. Goldberg

The creation of mouse models that recapitulate human diabetic cardiovascular disease remains a significant challenge. Part of the problem relates to the lack of a clear understanding of the human phenotype. Although improved insulin-treat of hyperglycemia reduces cardiovascular events in patients with type 1 diabetes, similar data are not available in type 2 diabetes. Moreover, whether human vascular disease is increased by hyperglycemia, defective insulin actions, or other factors is not known. Significant progress has been made in developing models of both type 1 and type 2 diabetes in mouse that can be used to study the relationship between hyperglycemia and atherosclerosis. This review describes mouse models that recapitulate specific aspects of diabetic dyslipidemia, hyperglycemia/insulin resistance, and diabetic vascular disease. Overall, the studies have clearly demonstrated that hyperlipidemia is a major driver of atherosclerotic vascular disease in the mouse. The effects of hyperglycemia and insulin resistance on murine atherosclerosis remain uncertain.


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The Influence of Acute Phase Proteins on Murine Atherosclerosis
G.D. Wool and C.A. Reardon

Atherosclerosis is a chronic inflammatory reaction that is initiated in response to hyperlipidemia and the retention and modification of lipids within the vascular wall. Chronic inflammatory states lead to steady low-level induction of the acute phase reaction and chronic inflammation is associated with elevated cardiovascular disease and atherosclerosis. The acute phase reaction is mediated by cytokines and results in significant changes in the plasma level of several proteins referred to as acute phase proteins. The liver is a major source of these proteins. Several recent studies in humans have shown that levels of acute phase proteins are modified in patients with established cardiovascular disease or are predictors of future disease. Whether these acute phase proteins are a biomarker of inflammation or have a direct role in the development of atherosclerosis is not clear. Murine models of atherosclerosis have been used to address the role of acute phase proteins in atherosclerosis. Modification of the expression level of these proteins has shown that the individual acute phase proteins are either pro-atherogenic or anti-atherogenic. The absence of an overall trend is perhaps not surprising given the complex nature of the acute phase response.


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Metabolic Syndrome as a Modifier of Atherosclerosis in Murine Models
M. Péterfy, R.C. Davis and A.J. Lusis

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 lipo-protein 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.