In the past few years, inflammation has emerged as a major driving force of atherosclerotic lesion development. It is now well-established that from early lesion to vulnerable plaque formation, numerous cellular and molecular inflammatory components participate in the disease process. The most prominent cells that invade in evolving lesions are monocyte-derived macrophages and T-lymphocytes. Both cell types produce a wide array of soluble inflammatory mediators (cytokines, chemokines) which are critically important in the initiation and perpetuation of the disease. This review summarizes the currently available information from mouse studies on the contribution of a specified group of cytokines expressed in atherosclerotic lesions, viz. interleukins (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12, IL-18, IL-20) and macrophage-associated cytokines [tumour necrosis factor-α (TNF-α); macrophage migration inhibitory factor (MIF); interferon-γ (IFN-γ); colony stimulating factors G-CSF,-M-CSF,-GM-CSF) to atherogenesis. Emphasis is put on the consistency of the effects of these cytokines, i.e. inasmuch an effect depends on the experimental approach applied (overexpression/deletion, strain, gender, dietary conditions, and disease stage). An important outcome of this survey is (i) that only for a few cytokines there is sufficient consistent data allowing classifying them as typically proatherogenic (IL-1, IL-12, IL-18, MIF, IFN-γ, TNF-α, and M-CSF) or antiatherogenic (IL-10) and (ii) that some cytokines (IL-4, IL-6 and GM-CSF) can exert pro- or anti-atherogenic effects depending on the experimental conditions. This knowledge can be used for improved early detection, prevention and treatment of atherosclerosis.

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...

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Background: Increased dietary cholesterol intake is associated with atherosclerosis. Atherosclerosis development requires a lipid and an inflammatory component. It is unclear where and how the inflammatory component develops. To assess the role of the liver in the evolution of inflammation, we treated ApoE*3Leiden mice with cholesterol-free (Con), low (LC; 0.25%) and high (HC; 1%) cholesterol diets, scored early atherosclerosis and profiled the (patho)physiological state of the liver using novel whole-genome and metabolome technologies.

The nuclear factor (NF)-kappaB is a primary regulator of inflammatory responses and may be linked to pathology associated with obesity. We investigated the progression of NF-kappaB activity during a 12-week feeding period on a high-fat diet (HFD) or a low-fat diet (LFD) using NF-kappaB luciferase reporter mice. In vivo imaging of luciferase activity showed that NF-kappaB activity was higher in the HFD mice compared with LFD-fed mice. Thorax region of HFD females displayed fourfold higher activity compared with LFD females, while no such increase was evident in males. In male HFD mice, abdominal NF-kappaB activity was increased twofold compared with the LFD males, while females had unchanged NF-kappaB activity in the abdomen by HFD. HFD males, but not females, exhibited evident glucose intolerance during the study. In conclusion, HFD increased NF-kappaB activity in both female and male mice. However, HFD differentially increased activity in males and females. The moderate increase in abdomen of male mice may be linked to glucose intolerance.

The aim of this study was to define the antiatherosclerotic role of liver-X-receptors (LXRs) under lesion progressive and lesion regressive conditions, to establish a temporal line of events, and to gain insights into the mechanisms underlying the anti-atherogenic potency of LXRs. We used apoE*3Leiden (E3L) mice to comprehensively and time-dependently dissect how T0901317, an LXR-agonist, inhibits initiation and progression of atherosclerotic lesions and regresses existing lipid-and macrophage-rich lesions. T0901317 suppresses lesion evolution and promotes lesion regression regarding lesion number, area, and severity. Quantitative plasma and vessel wall analyses corroborated by immunohistochemical evaluation of the aortic lesions revealed that under progressive (high-cholesterol diet) as well as regressive (cholesterol-free diet) conditions T0901317: i) significantly increases plasma triglyceride and total cholesterol levels; ii) does not affect the systemic inflammation marker, Serum amyloid A (SAA); iii) suppresses endothelial monocyte adhesion; and iv) induces the expression of the cholesterol efflux-related genes apolipoprotein E (apoE), ATP binding cassette (ABC) transporters ABCA1 and ABCG1. Furthermore, under progressive conditions, T0901317 suppresses the vascular inflammatory status (NF-kB) and the vascular expression of adhesion molecules [E-selectin, intercellular adhesion molecule (ICAM)-1, and CD44], lowers lesional macrophage accumulation, and blocks lesion evolution at the transition from lesional stage II to III. Under regressive conditions, T0901317 induces lesional macrophage disappearance and increases the expression of the chemokine receptor CCR7, a factor functionally required for regression. The LXR-agonist T0901317 retards vascular lesion development and promotes lesion regression at several levels.The findings support that vascular LXR is a potential antiatherosclerotic target.-Verschuren, L., J. de Vries-van der Weij, S. Zadelaar, R. Kleemann, and T. Kooistra. LXR agonist suppresses atherosclerotic lesion growth and promotes lesion regression in apoE*3Leiden mice: time course and mechanisms. J. Lipid Res. 2009. 50: 301-311.

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