Mouse models of atherosclerosis

Atherosclerosis is a complex disease in which progressive cellular changes occur for decades before the acute manifestation of cardiovascular disease. Definition of atherogenic mechanisms in humans is hindered by the complexity and chronicity of the disease process, combined with the inability to sequentially characterize lesions in an individual patient because of shortcomings in noninvasive detection modalities. Therefore, there has been a reliance on animal models of the disease to define mechanistic pathways. Over the last decade, the mouse has become the predominant species used to create models of atherosclerosis. The initial interest was based on the great diversity of inbred strains with defined genetic backgrounds that provides a means of linking genes to the development of atherosclerosis. More recently, the ability to genetically modify mice to over or under express specific genes has facilitated the definition of pathways in the atherogenic process. All of the current mouse models of atherosclerosis are based on perturbations of lipoprotein metabolism through dietary and/or genetic manipulations. Although hyperlipidemia is necessary for the development of atherosclerosis, mouse models have demonstrated that many nonlipid factors can influence the severity and characteristics of lesions. This review selectively highlights some of the most commonly used mouse models of atherosclerosis and compare their lesions to those formed in the human disease.     

Diabetic atherosclerosis mouse models

Coronary heart disease (CHD) due to atherosclerosis is the leading cause of death in the USA, and accelerated CHD has emerged as a leading cause of morbidity and mortality in diabetic patients in the USA and worldwide. This has highlighted the importance and urgency of studying the mechanism of diabetic atherosclerosis and exploring therapeutic options. Due to its unique advantages over other animal models, the mouse is the most used model for studying the mechanism of diabetes-accelerated atherosclerosis and exploring effective therapeutic approaches. In the past decade, several diabetic atherosclerosis mouse models have been established. Currently, however, there is no ideal animal model for diabetic atherosclerosis. To determine the characteristics of the models that more closely resemble human diabetic atherosclerosis disease, this review focuses on the common diabetic atherosclerosis mouse models with respect to the following issues: (1) whether the mice retain diabetic condition; (2) whether the diabetes accelerates atherosclerosis or increases atherogenic inflammation; (3) whether these factors respond to medical interventions. The discussion is aimed at identifying different diabetic mouse models and their features, in order to heighten awareness of the appropriate models that may provide useful tools for studying the mechanism of diabetes-accelerated atherosclerosis and evaluating therapeutic options.     

Diabetic vascular disease: an experimental objective

It is well known that humans with diabetes have more atherosclerosis and its complications. The causes of this relationship are, however, unclear. Although recent data show that improved glycemic control reduces arterial disease in type 1 diabetes, other studies have shown that subjects with "prediabetes" have more cardiovascular disease before the development of hyperglycemia. Thus, either hyperglycemia and/or lack of insulin actions are toxic to arteries, or metabolic derangements exclusive of hyperglycemia are atherogenic. For >50 years animal models of diabetes and atherosclerosis have been used to uncover potential mechanisms underlying diabetes associated cardiovascular disease. Surprisingly, diabetes alone increases vascular disease in only a few select animal models. Increased atherosclerosis has been found in several animals and lines of genetically modified mice; however, diabetes often also leads to greater hyperlipidemia. This makes it difficult to separate the toxic effects of insulin lack and/or hyperglycemia from those caused by the lipids. These studies are reviewed, as well as more recent investigations using new methods to create diabetic-atherosclerotic models.     

CXCL16/SR-PSOX--a friend or a foe in atherosclerosis?

Chemokines, scavenger receptors and adhesion molecules have long been known as important players in the pathogenesis of atherosclerosis. A series of studies conducted in the past few years described CXCL16/SR-PSOX--a new molecule combining those three functions, and suggested that CXCL16/SR-PSOX can be a potential player in atherogenesis. Initial ex vivo studies showed that CXCL16/SR-PSOX is abundant in human and murine atherosclerotic lesions. Following in vitro studies suggested that as an adhesion molecule CXCL16/SR-PSOX might mediate T-cell adhesion to the endothelium, as a chemokine - drive T-cell migration, stimulate cell proliferation and elicit inflammatory phenotype in smooth muscle cells (SMC) and, finally, as a scavenger receptor - mediate uptake of atherogenic lipoproteins by macrophages and SMC. All these effects are known to be pro-atherogenic. Surprisingly, in vivo studies performed in murine models of atherosclerosis suggested that CXCL16/SR-PSOX is atheroprotective, while its receptor CXCR6 is harmful. In addition, studies investigating the association of circulating CXCL16/SR-PSOX plasma concentrations with the presence and extent of coronary artery disease (CAD) in humans are controversial suggesting both positive, negative and no association. To finally answer the question whether CXCL16/SR-PSOX can serve as a causative factor, biomarker or even a therapeutic target in atherosclerosis, we are currently in need of carefully designed animal and human studies investigating the effects of CXCL16/SR-PSOX and CXCR6 deficiency, inhibition and over-expression on the progression of atherosclerosis. Such complex approach will help us unravel the mystery of CXCL16/SR-PSOX in atherosclerosis and hopefully develop better ways of treating atherosclerosis by targeting this interesting molecule.     

Experimental models of atherosclerosis. Contribution, limits and trends]

Experimental approaches to the problem of atherosclerosis involve animal or cellular models and procedures of lesional induction. Relevant animal models are rare. The rat, the mouse and the dog are free of "natural" atherosclerosis and only develop diffuse lipidosis after high cholesterol diet and thyroid block. They are more appropriate models of experimental arteriosclerosis and intimal proliferation induced by different procedures. The rabbit, also free of spontaneous atherosclerosis, is extremely sensitive to lipid-rich diets, but the lesions induced resemble more a xanthomatosis than an atherosclerosis. Immunological procedures in this model result in a generalised immune arteriosclerotic arteriopathy. The monkey and pig, which are phylogenetically close to man, develop spontaneous atherosclerosis exacerbated by lipid-rich diets or other procedures: hormones, psychosocial stress. The cost and problems of upkeep make these two models inaccessible to most laboratories. Although the hen, turkey and pigeon are grain-eating, they develop natural atherosclerosis, are sensitive to atherogenic diets, and provide satisfactory replacement models, especially for research into the viral and tumoral theories of atherogenesis. The pigeon is particularly suitable for studying cellular, biochemical and genetic aspects of atherosclerosis: these spontaneous plaques, similar to those in man, are ontogenetically and topographically predictable. The species include genetic types both sensitive and resistant to the disease. Moderately lipid-rich diets induce lesions even in very young pigeons. They also lend themselves well to the study of the antiatherosclerotic effects of pharmacological agents. Endothelial, smooth muscle and macrophage cell cultures are widely used to study the factors influencing cellular modulation and proliferation, lipid metabolism and movement of cholesterol, cellular biosynthesis and cell-cell and cell-matrix interactions.     

Mouse models for atherosclerosis and pharmaceutical modifiers

Atherosclerosis is a multifactorial highly-complex disease with numerous etiologies that work synergistically to promote lesion development. The ability to develop preventive and ameliorative treatments will depend on animal models that mimic the human subject metabolically and pathophysiologically and will develop lesions comparable to those in humans. The mouse is the most useful, economic, and valid model for studying atherosclerosis and exploring effective therapeutic approaches. Among the most widely used mouse models for atherosclerosis are apolipoprotein E-deficient (ApoE-/-) and LDL receptor-deficient (LDLr-/-) mice. An up-and-coming model is the ApoE*3Leiden (E3L) transgenic mouse. Here, we review studies that have explored how and to what extent these mice respond to compounds directed at treatment of the risk factors hypercholesterolemia, hypertriglyceridemia, hypertension, and inflammation. An important outcome of this survey is that the different models used may differ markedly from one another in their response to a specific experimental manipulation. The choice of a model is therefore of critical importance and should take into account the risk factor to be studied and the working spectrum of the compounds tested.     

Thiazolidinediones reduce the LDL binding affinity of non-human primate vascular cell proteoglycans

Aims/hypothesis Retention of atherogenic lipoproteins in the artery wall by proteoglycans is a key step in the development of atherosclerosis. Thiazolidinediones have been shown to reduce atherosclerosis in mouse models. The aim of this study was to determine whether thiazolidinediones modify vascular proteoglycan synthesis in a way that decreases LDL binding.Methods Primate aortic smooth muscle cells were exposed to troglitazone or rosiglitazone, or no stimulus at all for a 24-hour steady-state labelling period. Sulphate incorporation, size and LDL binding affinity of proteoglycans were determined. Proteoglycans secreted by cells in the presence or absence of troglitazone were separated into large and small classes by size exclusion chromatography, and LDL binding affinity was determined.Results Proteoglycans synthesised by cells exposed to troglitazone or rosiglitazone were smaller, with decreased sulphate incorporation and decreased LDL binding affinity. However, troglitazone had a greater effect than rosiglitazone. Troglitazone reduced the LDL binding affinities of both the large and small proteoglycans compared with control. The binding differences persisted when glycosaminoglycan chains released from proteoglycans were incubated with LDL, indicating that troglitazone affects the glycosaminoglycan synthetic machinery of these cells.Conclusions/interpretation Thiazolidinediones decrease the LDL binding affinity of the proteoglycans synthesised by primate aortic smooth muscle cells. This could, in part, account for the reduced atherosclerosis observed in animal models.Abbreviations PPAR peroxisome proliferator-activated receptor - K_d binding constantPresented in part at the 3rd Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology, Salt Lake City, Utah, USA, 6 April 2002     

Effects of ezetimibe on atherosclerosis in preclinical models

Ezetimibe (Zetia(?), Ezetrol(?), Merck, Whitehouse Station, NJ) is a potent inhibitor of sterol absorption, which selectively blocks the uptake of biliary and dietary cholesterol in the small intestine. Clinical trials have demonstrated the beneficial effects of ezetimibe on the reduction of atherogenic lipoproteins and the attainment of guideline-recommended lipid levels. Direct evidence that these improvements translate to a reduction in atherosclerosis or cardiovascular events is limited, although reductions in major atherosclerotic events that are consistent with the LDL-C lowering achieved have recently been presented for patients with chronic kidney disease treated with ezetimibe/simvastatin 10/20mg in the SHARP trial. Animal models of atherosclerosis have played a central role in defining the mechanisms involved in initiation and development of disease and have been used in drug development to evaluate potential therapeutic efficacy. The effect of ezetimibe on atherosclerosis has been examined in several of these animal model systems. ApoE knockout mice develop severe hypercholesterolemia and premature atherosclerosis with features similar to that seen in humans and techniques ranging from gross visualization of plaque to high-resolution MRI have demonstrated the consistent ability of ezetimibe to significantly inhibit atherosclerosis. sr-b1(-/-)/apoE(-/-) double knockout mice exhibit additional characteristics common to human coronary heart disease (CHD), and the one study of ezetimibe in sr-b1(-/-)/apoE(-/-) mice showed a significant reduction in aortic sinus plaque (57%), coronary arterial occlusion (68%), myocardial fibrosis (57%), and cardiomegaly (12%) compared with untreated controls. The effects of ezetimibe have also been evaluated in ldlr(-/-)/apoE(-/-) double knockout mice, demonstrating that functional LDL receptors were not required for ezetimibe-mediated reduction of plasma cholesterol or atherosclerosis. For the few studies that have been conducted in rabbits, ezetimibe has been shown to significantly inhibit diet and vascular-injury-induced atherosclerosis as measured by intima/media thickness, atherosclerotic lesion composition, and thrombosis. The current body of preclinical evidence consistently demonstrates that ezetimibe reduces atherosclerosis in animals, presumably due primarily to the decrease in circulating levels of atherogenic lipoproteins that the drug produces. Demonstration that ezetimibe-mediated lowering of atherogenic lipoproteins in humans has a similar effect on atherosclerosis and cardiovascular risk awaits additional results from recently completed and ongoing outcomes trials.     

Mechanisms of the atherogenic effects of elevated homocysteine in experimental models

Hyperhomocysteinemia is a risk factor for cardiovascular disease and stroke. During the last decade, considerable progress in delineating the mechanisms that underlie the atherogenic effects of hyperhomocysteinemia has been achieved through the use of experimental animal models. Among the most informative animal models are those that use genetic and dietary approaches to produce hyperhomocysteinemia in mice. Recent findings demonstrate that hyperhomocysteinemia can accelerate the development of atherosclerosis in susceptible models such as the apolipoprotein E-deficient mouse. Hyperhomocysteinemia also is a potent inducer of endothelial dysfunction, particularly in small vessels such as cerebral arterioles. Mechanisms of endothelial dysfunction may include inhibition of endothelial nitric oxide synthase by its endogenous inhibitor, asymmetric dimethylarginine, and oxidative inactivation of nitric oxide mediated by upregulation of prooxidant enzymes and downregulation of antioxidant enzymes. There also is good evidence from animal models that hyperhomocysteinemia produces endoplasmic reticulum stress, which may contribute to atherosclerosis and endothelial dysfunction by activating signal transduction pathways leading to inflammation, oxidative stress, and apoptosis.     

Noncoding RNAs as therapeutic targets in atherosclerosis with diabetes mellitus

Atherosclerosis is one of the major macrovascular complications of diabetes mellitus (DM), and it is the main cause of death from clinical observation. Among various cell types involved in this disorder, endothelial cells, vascular smooth muscle cells (VSMCs), and macrophages play a crucial role in the occurrence and development of this disease. The regulation and stabilization of these cells are a key therapeutic strategy for DM‐associated atherosclerosis. An increasing number of evidences implicate that various types of noncoding RNAs (ncRNAs) play a vital role in many cellular responses as well as in physiological and pathological processes of atherosclerosis and DM that drive atherogenic/antiatherogenic processes in those cells. Encouragingly, many ncRNAs have already been tested in animal experiments or clinical trials showing good performance. In this review, we summarize recent progresses in research on functional regulatory role of ncRNAs in atherosclerosis with DM. More importantly, we illustrate new thoughts and findings relevant to ncRNAs as potential therapeutic targets or biomarkers for atherosclerosis with DM.     

Cholesterol reduction and atherosclerosis inhibition by bezafibrate in low-density lipoprotein receptor knockout mice

Fibrates, peroxisome proliferator-activated receptor a agonists, are widely used as lipid-lowering agents with anti-atherogenic activity. However, conflicting results have been reported with regard to their pharmacological effects on plasma lipoprotein profiles as well as on atherosclerosis in animal models. Furthermore, the anti-atherogenic effects of bezafibrate, one of the most commonly used fibrates, in animal models have not been reported. In the present study, we investigated the effects of bezafibrate on lipoprotein profiles as well as on atherosclerosis in low-density lipoprotein receptor knockout (LDLR-/-) mice fed an atherogenic diet for 8 weeks. Bezafibrate decreased plasma levels of both cholesterol and triglycerides (TG), while increasing plasma levels of high-density lipoprotein-cholesterol (HDL-C). Since hepatic TG production was significantly reduced in the bezafibrate-treated mice lacking LDLR, the plasma lipid-lowering effects of bezafibrate might be primarily mediated by the suppression of hepatic production of apolipoprotein-B-containing lipoproteins. In parallel with the reduced ratio of non-HDL-C to HDL-C, bezafibrate suppressed fatty streak lesions in the aortic sinus by 51%. To determine whether or not bezafibrate directly alters the expression of genes relevant to atherosclerosis, we measured mRNA expression levels of three genes in the aorta by real-time PCR: ATP-binding cassette transporter A1, lipoprotein lipase, and monocyte chemoattractant protein-1. The results showed that there were no differences in the expression of these genes between mice treated with bezafibrate and those not. In conclusion, bezafibrate inhibits atherosclerosis in LDLR-/- mice primarily by decreasing the ratio of non-HDL-C to HDL-C.     

Diet and murine atherosclerosis

Lipid-enriched diets are often used to induce or accelerate the rate of atherosclerotic lesion development in murine models of atherosclerosis. It appears that the induction of persistent hypercholesterolemia to levels > or approximately to 300 mg/dL is required for the development of experimental atherosclerosis in the mouse. A variety of different diets have been used that vary in the level of cholesterol, the level and type of fatty acid, and the absence or presence of cholate. Each of these components as well as the protein source has been shown to influence lipoprotein level and/or atherosclerosis, with dietary cholesterol being the major proatherogenic component. In some instances the effects of these components on the expression of hepatic genes relevant to lipid homeostasis has been observed. An appreciation of the effect of the differences in diet composition on these processes is important to compare results from different atherosclerosis studies, so the composition of the diets used should always be reported or referenced. Cholate should not be used unless its effects are being specifically investigated.     

The potential role of AT(1)-receptor blockade in the prevention and reversal of atherosclerosis

The renin-angiotensin system may contribute to the development and progression of atherosclerosis both by increasing blood pressure and by direct effects on all phases of the atherogenic process. Genetic determinants of renin-angiotensin system activation, notably the DD genotype of angiotensin converting enzyme (ACE), are associated with an increased risk of cardiovascular events, as is increased plasma renin activity. In addition, angiotensin II has been shown to increase the uptake and oxidation of low density lipoprotein (LDL) by macrophages and endothelial cells. Angiotensin II also stimulates the production of interleukin 6 and activates the pro-inflammatory factor nuclear factor kappa(B), leading to expression of adhesion molecules and recruitment of monocytes and macrophages, and increases the production of pro-coagulatory factors. In animal experiments, treatment with ACE inhibitors or angiotensin AT(1)-receptor blockers has been shown to have anti-atherogenic effects. Studies with candesartan have shown that this agent produces a dose-dependent reduction in uptake of oxidised LDL by mouse macrophages in vitro, and reduces cholesterol accumulation and atherosclerosis development in the aorta of Watanabe rabbits. These effects were independent of changes in blood pressure. Such findings suggest that AT(1)-receptor blockers may be beneficial in reducing mortality and morbidity resulting from atherosclerotic disease, and are consistent with the findings from large outcome trials with ACE inhibitors in patients at risk of cardiovascular events.     

Inflammatory reactions in the pathogenesis of atherosclerosis

Atherosclerosis and its complications constitute the most common causes of death in Western societies and Japan. Although several theories or hypotheses about atherogenesis have been proposed during the past decades, none can completely explain the whole process of the pathogenesis of atherosclerosis because this disease is associated with multiple risk factors. In spite of this, the concept that atherosclerosis is a specific form of chronic inflammatory process resulting from interactions between plasma lipoproteins, cellular components ( monocyte/macrophages, T lymphocytes, endothelial cells and smooth muscle cells ) and the extracellular matrix of the arterial wall, is now well accepted. Histologically, atherosclerotic lesions from the early-stage ( fatty streak ) to more complicated lesions possess all the features of chronic inflammation. It has been demonstrated that atherogenic lipoproteins such as oxidized low density lipoprotein ( LDL ), remnant lipoprotein (beta-VLDL) and lipoprotein [ Lp ] ( a ) play a critical role in the pro-inflammatory reaction, whereas high density lipoprotein ( HDL ), anti-atherogenic lipoproteins, exert anti-inflammatory functions. In cholesterol-fed animals, the earliest events in the arterial wall during atherogenesis are the adhesion of monocytes and lymphocytes to endothelial cells followed by the migration of these cells into the intima. It has been shown that these early events in atherosclerosis are triggered by the presence of high levels of atherogenic lipoproteins in the plasma and are mediated by inflammatory factors such as adhesion molecules and cytokines in the arterial wall. The development of genetically modified laboratory animals ( transgenic and knock-out mice and transgenic rabbits ) has provided a powerful approach for dissecting individual candidate genes and studying their cause-and-effect relationships in lesion formation and progression. The purpose of this article is to review the recent progress regarding the inflammatory processes during the development of atherosclerosis based on both human and experimental studies. In particular, we will address the mechanisms of atherogenic lipoproteins in terms of inflammatory reactions associated with hypercholesterolemia. Understanding the molecular mechanisms responsible for inflammatory reactions during atherogenesis may help us to develop novel therapeutic strategies to control, treat and prevent atherosclerosis in the future.     

Genetic manipulation of hematopoietic stem cells

Over the past two decades, the ability to transfer genes into hematopoietic stem cells (HSCs) has provided new insights into the behavior of individual stem cells and offered a novel approach for the treatment of various inherited or acquired disorders. At present, gene transfer into HSCs has been achieved mainly using modified retroviruses. While retrovirus-based vectors could efficiently transduce murine HSCs, extrapolation of these methods to large mammals and human clinical trials resulted in very low numbers of gene-marked engrafted cells. In addition, in vitro progenitor assays used to optimize gene transfer procedures were found to poorly predict the outcome of stem cell gene transfer. The focus rapidly turned to the development of superior and more relevant preclinical assays in human stem cell gene transfer research. Xenogeneic transplant models and large animal transplantation system have been invaluable. The development of better assays for evaluating human gene therapy protocols and a better understanding of stem cell and vector biology has culminated over the past decade in multiple strategies to improve gene transfer efficiency into HSCs. Improved gene transfer vectors, optimization of cytokine combination, and incorporation of a recombinant fragment of fibronectin during transduction are examples of novel successful additions to the early gene transfer protocols that have contributed to the first unequivocal clinical benefits resulting from genetic manipulation of HSC.     

Animal models of spontaneous plaque rupture: The holy grail of experimental atherosclerosis research

Throughout the history of atherosclerosis research we have sought animal models of the disease process that exhibit high frequencies of the features that make human plaque a clinical risk: plaque rupture, mural thrombosis, and intra-plaque hemorrhage. This type of model is needed to determine the mechanisms by which plaques rupture and to design and test therapeutic interventions for stabilizing plaques. Studies of domestic and exotic animals have shown that most species will spontaneously develop fatty streaks and in some cases atheromatous lesions with sufficient time, but that rupture and thrombosis is exceedingly rare. Even with addition of fat and cholesterol to the diet, lesion development is accelerated but does not increase the frequency with which plaques rupture in most animal models. However, recently we have observed high frequencies of intra-plaque hemorrhage in the innominate/brachiocephalic arteries of older, chow-fed, hyperlipidemic, apolipoprotein E-deficient mice, and high frequencies of plaque rupture with mural thrombus in younger apolipoprotein E-deficient mice fed a high-fat diet. This suggests that plaque rupture and secondary thrombosis are frequent and reproducible occurrences at specific sites in apolipoprotein E-deficient mice, and that the timing and pathobiology of the ruptures are influenced by lipid status in this murine model.     

Inflammation associated with the postprandial lipolysis of triglyceriderich lipoproteins by lipoprotein lipase

Although hypertriglyceridemia has repeatedly been implicated as an atherogenic condition, there are conflicting reports concerning the atherogenicity of products released from triglyceride-rich lipoproteins by lipoprotein lipase. The hydrolysis of triglyceride is a normal process by which chylomicrons and very low-density lipoproteins are metabolized and cleared from the circulation, which would suggest a beneficial role for lipoprotein lipase in reducing circulating levels of triglyceride and, therefore, reducing atherosclerotic burden. However, many in vitro studies have shown that lipolysis products such as fatty acids induce vascular cell inflammation, which can initiate or exacerbate atherosclerosis. This review summarizes the results and implications of recent studies on the effects of lipoprotein lipase on vascular inflammation, expanding upon existing controversy among human postprandial studies, animal models, and in vitro experimental models.     

Genetic Variants of the Renin Angiotensin System: Effects on Atherosclerosis in Experimental Models and Humans

The renin angiotensin system (RAS) has profound effects on atherosclerosis development in animal models, which is partially complimented by evidence in the human disease. Although angiotensin II was considered to be the principal effector of the RAS, a broader array of bioactive angiotensin peptides have been identified that have increased the scope of enzymes and receptors in the RAS. Genetic interruption of the synthesis of these peptides has not been extensively performed in experimental or human studies. A few studies demonstrate that interruption of a component of the angiotensin peptide synthesis pathway reduces experimental lesion formation. The evidence in human studies has not been consistent. Conversely, genetic manipulation of the RAS receptors has demonstrated that AT1a receptors are profoundly involved in experimental atherosclerosis. Few studies have reported links of genetic variants of angiotensin II receptors to human atherosclerotic diseases. Further genetic studies are needed to define the role of RAS in atherosclerosis.     

Accelerated atherosclerosis and calcification in vein grafts: a study in APOE*3 Leiden transgenic mice

Vein grafts fail due to development of intimal hyperplasia and accelerated atherosclerosis. Many murine genetic models in which genes are overexpressed, deleted, or mutated have been introduced recently. Therefore, mouse models are very well suited to dissect the relative contribution of different genes in the development of accelerated atherosclerosis. In the present study, we evaluated whether accelerated atherosclerosis in human vein grafts could be mimicked in hypercholesterolemic APOE*3 Leiden transgenic mice. Venous bypass grafting was performed in the carotid artery in APOE*3 Leiden mice fed either a standard chow diet or a high cholesterol-rich diet for 4 weeks. At several time points (0 hour to 28 days), mice were euthanized and the morphology of the vein grafts was analyzed. In normocholesterolemic mice, vein graft thickening up to 10-fold original thickness, predominantly consisting of alpha-smooth muscle cell actin-positive cells, was observed after 28 days. In hypercholesterolemic mice, accelerated atherosclerosis with accumulation of lipid-loaded foam cells was observed within 7 days after surgery. This accelerated atherosclerosis progressed in time and resulted in significant increase in vein graft thickening up to 50 times original thickness with foam cell-rich lesions and calcification within 28 days after surgery. The atherosclerotic lesions observed in these murine grafts show high morphological resemblance with the atherosclerotic lesions observed in human vein grafts. This accelerated, diet-dependent induction of atherosclerotic-like lesions in murine vein grafts provides a valuable tool in evaluating the mechanisms of accelerated atherosclerosis and therapeutic interventions of vein graft disease.     

Lipid inflammatory mediators in diabetic vascular disease

Type 2 diabetes is associated with significantly accelerated rates of macrovascular complications such as atherosclerosis. Emerging evidence now indicates that atherosclerosis is an inflammatory disease and that certain inflammatory markers may be key predictors of diabetic atherosclerosis. Proinflammatory cytokines and cellular adhesion molecules expressed by vascular and blood cells during stimulation by growth factors and cytokines seem to play major roles in the pathophysiology of atherosclerosis and diabetic vascular complications. However, more recently, data suggest that inflammatory responses can also be elicited by smaller oxidized lipids that are components of atherogenic oxidized low-density lipoprotein or products of phospholipase activation and arachidonic acid metabolism. These include oxidized lipids of the lipoxygenase and cyclooxygenase pathways of arachidonic acid and linoleic acid metabolism. These lipids have potent growth, vasoactive, chemotactic, oxidative, and proinflammatory properties in vascular smooth muscle cells, endothelial cells, and monocytes. Cellular and animal models indicate that these enzymes are induced under diabetic conditions, have proatherogenic effects, and also mediate the actions of growth factors and cytokines. This review highlights the roles of the inflammatory cyclooxygenase and 12/15-lipoxygenase pathways in the pathogenesis of diabetic vascular disease. Evidence suggests that inflammatory responses in the vasculature can be elicited by small oxidized lipids that are components of oxidized low-density lipoprotein or products of the lipoxygenase and cyclooxygenase pathways of arachidonic and linoleic acid metabolism. This review evaluates these inflammatory and proatherogenic pathways in the pathogenesis of diabetic vascular disease.