The cytokine macrophage migration inhibitory factor (MIF) plays a critical role in inflammatory diseases and atherogenesis. We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF. MIF triggered G(alphai)- and integrin-dependent arrest and chemotaxis of monocytes and T cells, rapid integrin activation and calcium influx through CXCR2 or CXCR4. MIF competed with cognate ligands for CXCR4 and CXCR2 binding, and directly bound to CXCR2. CXCR2 and CD74 formed a receptor complex, and monocyte arrest elicited by MIF in inflamed or atherosclerotic arteries involved both CXCR2 and CD74. In vivo, Mif deficiency impaired monocyte adhesion to the arterial wall in atherosclerosis-prone mice, and MIF-induced leukocyte recruitment required Il8rb (which encodes Cxcr2). Blockade of Mif but not of canonical ligands of Cxcr2 or Cxcr4 in mice with advanced atherosclerosis led to plaque regression and reduced monocyte and T-cell content in plaques. By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. Targeting MIF in individuals with manifest atherosclerosis can potentially be used to treat this condition.

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...

Suppression of inflammation, manipulation of coagulation as well as direct augmentation of fibrinolytic activity may be promising antiadhesion treatment strategies.

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