Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophage migration inhibitory factor (MIF), a cytokine originally reported in the 1960s as the prototypic T lymphokine, has emerged in recent years as a key factor regulating inflammatory responses. Both by directly activating immune cells, and by participating in activation entrained by other stimuli, MIF is important in innate and adaptive immune responses as well as tissue-specific mechanisms of damage. As a consequence of its involvement in multiple stages of the immune-inflammatory response, MIF has the potential to be involved in the pathogenesis of a range of immune-mediated inflammatory diseases affecting multiple organ systems. Diseases in which a role for MIF has been strongly validated include rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, atherosclerosis, asthma, inflammatory liver disease, and most recently systemic lupus erythematosus. Recent data have provided mechanisms of action for MIF which further support its suitability as a therapeutic target. Finally, MIF has a unique relationship with glucocorticoids, acting to counter-regulate their anti-inflammatory effects, such that MIF antagonist therapy may be a direct route to 'steroid-sparing'. Methods of targeting MIF therapeutically have also emerged in recent years, based on the unique protein structure of MIF which affords opportunities for direct antagonism by small molecules, as well as by protein therapeutics such as monoclonal antibodies. Clinical trials of MIF antagonist therapies are likely before the end of the current decade.
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PMID:Macrophage migration inhibitory factor: a therapeutic target across inflammatory diseases. 1789 55

The past decade has seen the emergence of two new paradigms in inflammatory disease: first, cardiovascular complications of atherosclerosis are markedly increased in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE); and second, inflammatory mechanisms are important in the pathogenesis of atherosclerosis. These concurrent developments have lead to the concept that inflammatory mediators operative in RA and SLE might be causal in the accelerated atherosclerosis observed, a concept supported by clinical studies showing that this acceleration is not fully explained by traditional vascular risk factors. Separate lines of evidence implicate the cytokine macrophage migration inhibitory factor (MIF) in RA, SLE, and atherosclerosis. Several reports have revealed definitive in vivo evidence of the activity of MIF in a model of SLE, demonstrated a novel role for MIF in monocyte/macrophage recruitment, and showed that MIF regulates a key mediator of inflammatory cell activation. Together with evidence that MIF circulates in increased concentrations in patients with RA and SLE, this information suggests that in addition to contributing to each disease, MIF might contribute directly to the acceleration of atherosclerosis in RA and SLE.
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PMID:Mechanisms of disease: macrophage migration inhibitory factor in SLE, RA and atherosclerosis. 1823 39

Peroxisome proliferator-activated receptor-gamma1 (PPARgamma1) is an important transcription factor involved in atherosclerosis progression. Thus, PPARgamma1 appears to be an interesting gene therapeutic target to favorably affect atherosclerosis development. The present study was carried out to test the hypothesis that PPARgamma1 gene therapy may attenuate and stabilize atherosclerotic plaques in apolipoprotein E-knockout mice. The recombinant adenovirus carrying mouse PPARgamma1 cDNA (AdPPARgamma1) was constructed and AdPPARgamma1 (5 x 10(8) PFU) or AdGFP (5 x 10(8) PFU), diluted to a total volume of 200 mul, was injected into the tail vein of mice (40 weeks of age and fed a high-fat diet) in two intervention groups (n = 20 each). Mice (n = 20) injected with phosphate-buffered saline (PBS) served as vehicle controls. The results showed that 4-week treatment with AdPPARgamma1 attenuated atherosclerotic lesions, although the overall mRNA levels of CD36 were increased in the AdPPARgamma1 group. Moreover, PPARgamma1 gene overexpression stabilized atherosclerotic plaques as shown by the reduced depositions of lipids and macrophages and increased contents of smooth muscle cells and collagen within the plaques. In addition, marked upregulation of the mRNA levels of cholesterol efflux-related molecules such as liver X receptor alpha and ATP-binding cassette transporter A1 in liver, and downregulation of matrix metalloproteinase-9, human tissue factor, CD40, CD40 ligand, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, macrosialin, class A scavenger receptor, and macrophage migration inhibitory factor in aorta, were demonstrated in AdPPARgamma1-treated animals. In contrast, there was no significant difference in aforementioned parameters between the AdGFP and PBS groups. In conclusion, overexpression of the PPARgamma1 gene exerts beneficial effects in attenuating atherosclerosis progression and stabilizes vulnerable plaques. Thus, PPARgamma1 might offer a promising gene therapeutic target against atherosclerosis.
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PMID:Peroxisome proliferator-activated receptor-gamma1 gene therapy attenuates atherosclerosis and stabilizes plaques in apolipoprotein E-deficient mice. 1830 11

The highly conserved and archetypical yet atypical cytokine macrophage migration inhibitory factor (MIF) fulfills pleiotropic immune functions in many acute and chronic inflammatory diseases. Recent evidence has emerged from both expression and functional studies to implicate MIF in various aspects of cardiovascular disease. The present review is aimed at providing a synopsis of the involvement of MIF in the inflammatory pathogenesis of atherosclerosis and its consequences, namely unstable plaque formation, remodeling after arterial injury, aneurysm formation, myocardial infarction, or ischemia-reperfusion injury. In addition, other forms of myocardial dysfunction and inflammation and the role of MIF in angiogenesis are reviewed. The functional data are reconciled with recent progress in the identification of heptahelical (CXC chemokine) receptors for MIF, its prototypic role as their noncanonical ligand, and its signal transduction profile operative in atherogenic and inflammatory recruitment of mononuclear cells and in the oxidative damage and apoptosis of cardiomyocytes. Its unique features and functions clearly distinguish MIF from other cytokines implicated in atherogenesis and make it a prime target for achieving therapeutic regression of atherosclerosis. The potential of targeting or exploiting MIF for therapeutic strategies or as a diagnostic marker in the management of cardiovascular diseases or disorders is scrutinized.
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PMID:Macrophage migration inhibitory factor in cardiovascular disease. 1836 43

The cytokine macrophage migration inhibitory factor (MIF) is a unique pro-inflammatory regulator of many acute and chronic inflammatory diseases. In the pathogenesis of atherosclerosis, chronic inflammation of the arterial wall characterized by chemokine-mediated influx of leukocytes plays a central role. The contribution of MIF to atherosclerotic vascular disease has come into focus of many studies in recent years. MIF is highly expressed in macrophages and endothelial cells of different types of atherosclerotic plaques, and functional studies established the contribution of MIF to lesion progression and plaque inflammation. This proatherogenic effect may partly be explained by the finding that MIF regulates inflammatory cell recruitment to lesion areas. Similar to chemokines, MIF induces integrin-dependent arrest and transmigration of monocytes and T cells. These chemokine-like functions are mediated through interaction of MIF with the chemokine receptors CXCR2 and CXCR4 as a non-canonical ligand. In atherogenic monocyte recruitment, MIF-induced monocyte adhesion involves CD74 and CXCR2, which form a signaling receptor complex. In addition to lesion progression, MIF has been implicated in plaque destabilization, since MIF is predominantly expressed in vulnerable plaques and can induce collagen-degrading matrix metalloproteinases. The latter could be a relevant mechanism in atherosclerotic abdominal aneurysm formation, where MIF expression is correlated with aneurysmal expansion. In summary, MIF has been identified as an important regulator of atherosclerotic vascular disease with exceptional chemokine-like functions. Detailed analysis of the interaction of MIF with its receptors could provide valuable information for drug development for the anti-inflammatory treatment of established and unstable atherosclerosis.
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PMID:Chemokine-like functions of MIF in atherosclerosis. 1838 67

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-alpha (TNF-alpha); macrophage migration inhibitory factor (MIF); interferon-gamma (IFN-gamma); 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-gamma, TNF-alpha, 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.
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PMID:Cytokines and atherosclerosis: a comprehensive review of studies in mice. 1848 33

Originally discovered and named as an in vitro inhibitor of macrophage migration, the cytokine macrophage migration inhibitory factor (MIF) has now been shown to be a key regulator of acute and chronic immuno-inflammatory conditions including rheumatoid arthritis (RA), atherosclerosis, and more recently systemic lupus erythematosus (SLE). Common inflammatory events in these diseases include activation of cells and infiltration by immune cells at the site of injury. MIF actively participates in multiple stages of the inflammatory response, acting on cells directly and/or potentiating the effects entrained by other stimuli. The overlap of inflammatory processes operating in these diseases, the known activities of MIF, and the observation of atherosclerosis as a major comorbidity of RA and SLE, make MIF a strong candidate for therapeutic targeting in these diseases. Moreover, the unique relationship between MIF and glucocorticoids, commonly used in the treatment of RA and SLE but associated with significant side effects, highlights the potential of MIF as a 'steroid sparing' therapeutic target encompassing all three conditions.
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PMID:Macrophage migration inhibitory factor: a key cytokine in RA, SLE and atherosclerosis. 1883 66

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(-/-)) mouse model of disease. Ldlr(-/-) mice develop IR and glucose intolerance within 15 weeks, whereas Mif(-/-)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.
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PMID:MIF deficiency reduces chronic inflammation in white adipose tissue and impairs the development of insulin resistance, glucose intolerance, and associated atherosclerotic disease. 1947

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine playing important roles in atherosclerosis. MIF gene deficiency and neutralizing antibodies against MIF have been reported to exert anti-atherosclerotic effects in various animal models. However, the mechanism by which MIF is induced in atherosclerotic lesions remains unclear. In the present studies, we cloned a 540bp full-length rabbit MIF cDNA by screening a rabbit uterine library. The cDNA contains a 348bp open-reading frame which encodes a deduced 115-amino acid polypeptide with approximately 90% similarity to human and mouse homologs. Constitutive MIF mRNA expression was detected in most rabbit tissues including aortas. The expression of MIF obviously abounded in vascular smooth muscle cells (VSMCs) of the atherosclerotic plaques. In cultured VSMCs, MIF expression was significantly induced by a pro-atherogenic factor, oxidized low-density lipoprotein (oxLDL). Promoter analysis showed there were two NF-kappaB binding sites in the MIF proximal promoter region. Deletion or mutation of the two sites abolished oxLDL-enhanced MIF promoter activity. Moreover, the induction of MIF by oxLDL can be blocked by IkappaB-alpha overexpression. Taken together, our results revealed that MIF expression can be induced by oxLDL in VSMCs via a NF-kappaB dependent manner, which may contribute to the pathogenesis of atherosclerosis.
Atherosclerosis 2009 Dec
PMID:Induction of MIF expression by oxidized LDL via activation of NF-kappaB in vascular smooth muscle cells. 1964 May 36

In the recent years, atherogenesis has increasingly been linked to inflammatory processes in the injured vessel wall. Recruitment and arrest of monocytes, T cells, and neutrophils via the concerted actions of multiple chemokines and their chemokine receptors have been the subject of intense research and are being appreciated as key events underlying atherosclerotic lesion formation and progression. The evolutionary conserved cytokine macrophage migration inhibitory factor (MIF) exhibits prominent proinflammatory and proatherogenic functions, and the latest findings on its chemotactic and chemokine-like properties imply MIF as a crucial drug target for the treatment of inflammatory diseases. In this review, the role of MIF in atherosclerosis and injury-induced neointima formation is discussed. We place an emphasis on its proinflammatory and chemokine-like functions in the context of underlying extra- and intracellular signaling mechanisms. These findings clearly distinguish MIF from other cytokines in atherosclerosis and justify the intensive search for inhibitors targeting MIF in the treatment of inflammatory diseases, including advanced atherosclerosis.
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PMID:Macrophage migration inhibitory factor: a noncanonical chemokine important in atherosclerosis. 1967 64


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