Abstract-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 Ϫ/Ϫ ) and LDL receptor-deficient (LDLr Ϫ/Ϫ ) 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. Key Words: mouse models Ⅲ atherosclerosis Ⅲ pharmaceutical drugs Ⅲ statins Ⅲ ACE inhibitors Ⅲ AT 1 receptor antagonists Ⅲ PPAR Ⅲ LXR D espite significant advances in treatment and in understanding of its biology, coronary atherosclerosis remains the leading cause of morbidity and mortality of men and women in industrialized societies. Hypercholesterolemia, particularly of low-density lipoprotein (LDL) cholesterol and very low-density lipoprotein (VLDL) cholesterol, is a wellestablished risk factor for the incidence of atherosclerosis and its pathologic complications. For the past 20 years, the statin class of cholesterol-lowering drugs has been the mainstay for the treatment of hypercholesterolemia ( 1 and references therein). However, despite the success of statins in effectively lowering cholesterol levels and reducing cardiovascular causes of death, two thirds of the statin-treated patients still experience adverse coronary events.In recent years, there has been a significant push toward the development of new therapeutics that target risk factors other than hypercholesterolemia and that can be used alone or in combination with a statin. Among the new drug targets are "traditional" risk factors discovered by classical epidemiology and which include, besides hypercholesterolemia, hypertriglyceridemia, low high-density lipoprotein (HDL), hypertension, insulin resistance, and type-2 diabetes. Furthermore, there is increasing evidence for a contribution of systemic and local (ie, vascular) inflammatory processes to atherogenesis, indicating that chronic inflammation is a requirement for the progression of atherosclerosis in patients. 2 Definition of atherogenic mechanisms in humans is hindered by the complexity and chronicity of the disease process. Another complication is th...

Abstract-Chronic inflammation in white adipose tissue (WAT) is positively associated with obesity, insulin resistance (IR) and the development of type 2 diabetes. The proinflammatory cytokine MIF (macrophage migration inhibitory factor) is an essential, upstream component of the inflammatory cascade. This study examines whether MIF is required for the development of obesity, IR, glucose intolerance, and atherosclerosis in the LDL receptor-deficient (Ldlr littermates are protected. MIF deficiency does not affect obesity and lipid risk factors but specifically reduces inflammation in WAT and liver, as reflected by lower plasma serum amyloid A and fibrinogen levels at baseline and under inflammatory conditions. Conversely, MIF stimulates the in vivo expression of human C-reactive protein, an inflammation marker and risk factor of IR and cardiovascular disease. In WAT, MIF deficiency reduces nuclear c-Jun levels and improves insulin sensitivity; MIF deficiency also reduces macrophage accumulation in WAT and blunts the expression of two proteins that regulate macrophage infiltration (intercellular adhesion molecule-1, CD44). Mechanistic parallels to WAT were observed in aorta, where the absence of MIF reduces monocyte adhesion, macrophage lesion content, and atherosclerotic lesion size. These data highlight the physiological importance of chronic inflammation in development of IR and atherosclerosis and suggest that MIF is a potential therapeutic target for reducing the inflammatory component of metabolic and cardiovascular disorders. Key Words: inflammation Ⅲ cytokines Ⅲ atherosclerosis Ⅲ insulin resistance Ⅲ C-reactive protein T he intertwined medical problems of obesity, glucose intolerance, type 2 diabetes (T2D), dyslipidemia, and atherosclerosis form the most serious threats to public health worldwide. Insulin resistance (IR) is an integral feature of the medical sequelae that are collectively referred to as the metabolic syndrome. 1 Decreased insulin sensitivity is the underlying defect in Ͼ90% of patients with T2D, and it is also considered to be a major pathological mechanism for the associated development of cardiovascular disease. 2 Recent human and animal studies have established both correlative and causative links between IR and chronic inflammation, in particular within adipose tissue. 3,4 For example, C-reactive protein (CRP), which is a serum marker of systemic inflammation, is independently related to insulin insensitivity and highly predictive for progression to overt T2D. 5 Mechanistic studies that have evaluated the impact of blocking specific inflammatory control points, such as c-Jun N-terminal kinase (JNK)1, 6 support the concept that the persistent activation of proinflammatory transcription factors (eg, c-Jun) in critical metabolic sites (adipose and liver tissue) may underlie the development of IR. When chronically inflamed, these tissues release proinflammatory molecules, including cytokines, acute-phase reactants, and procoagulant factors (eg, interleukin [IL]-6, serum amyloid A [SAA]...

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Background-Although cholesteryl ester transfer protein (CETP) inhibition is regarded as a promising strategy to reduce atherosclerosis by increasing high-density lipoprotein cholesterol, the CETP inhibitor torcetrapib given in addition to atorvastatin had no effect on atherosclerosis and even increased cardiovascular death in the recent Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events trial. Therefore, we evaluated the antiatherogenic potential and adverse effects of torcetrapib in humanized APOE*3-Leiden.CETP (E3L.CETP) mice. Methods and Results-E3L.CETP mice were fed a cholesterol-rich diet without drugs or with torcetrapib (12 mg · kg Ϫ1 · d Ϫ1 ), atorvastatin (2.8 mg · kg Ϫ1 · d