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)

Sustained proinflammatory responses in rheumatoid arthritis, atherosclerosis, and diabetic retinopathy, as well as in cancer, are often associated with increased angiogenesis that contributes to tissue disruption and disease progression. High mobility group B1 (HMGB1) has been recognized as a proinflammatory cytokine and more recently, as a proangiogenic factor. HMGB1 can either be passively released from necrotic cells or actively secreted in response to angiogenic and inflammatory signals. HMGB1 itself may signal through the receptor for advanced glycation end products (RAGE), and via toll-like receptors, TLR2 and TLR4. Activation of these receptors results in the activation of NFkappaB, which induces the upregulation of leukocyte adhesion molecules and the production of proinflammatory cytokines and angiogenic factors in both hematopoietic and endothelial cells, thereby promoting inflammation. Interestingly, HMGB1 seems to be involved in a positive feedback mechanism, that may help to sustain inflammation and angiogenesis in several pathological conditions, thereby contributing to disease progression. Endothelial cells express HMGB1, as well as the receptors RAGE, TLR2, and TLR4, and in diverse pathologies HMGB1 and its receptors are overexpressed. Furthermore, HMGB1-induced signaling can activate NFkappaB, which can subsequently induce the expression of HMGB1 receptors. Thus, HMGB1 can mediate amplification of inflammation and angiogenesis through increased secretion of HMGB1 and increased expression of the receptors it can interact with. In this review, we discuss signaling cascades that HMGB1 can induce via TLRs and RAGE, as well as its contribution to pathologies involving endothelial cells.
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PMID:Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1). 1826 87

Acute coronary syndromes (ACS) are characterized by multiple unstable coronary plaques and elevated circulating levels of inflammatory biomarkers. The endothelium of internal mammary arteries (IMA), which are atherosclerosis resistant, is exposed to proinflammatory stimuli as vessels that develop atherosclerosis. Our study investigated the IMA endothelial expression of inflammatory molecules in patients with ACS or chronic stable angina (CSA). IMA demonstrated normal morphology, intact endothelial lining, and strong immunoreactivity for glucose transporter 1. E-selectin expression was observed more frequently in IMA of ACS patiention than CSA patients (ACS 61% vs. CSA 14%, P = 0.01). High fluorescence for major histocompatibility complex (MHC) was significantly more frequent on the luminal endothelium (ACS 66.7% vs. CSA 17.6%, P = 0.001 for class I; and ACS 66.7% vs. CSA 6.2%, P = 0.0003 for class II-DR) and on the vasa vasorum (ACS 92.9% vs. CSA 33.3% and 7.7%, P = 0.0007 and P < 0.0001 for class I and class II-DR, respectively) of ACS patients than CSA patients. ICAM-1, VCAM-1, Toll-like receptor 4, tissue factor, IL-6, inducible nitric oxide synthase, and TNF-alpha expression were not significantly different in ACS and CSA. Circulating C-reactive protein [ACS 4.8 (2.6-7.3) mg/l vs. CSA 1.8 (0.6-3.5) mg/l, P = 0.01] and IL-6 [ACS 4.0 (2.6-5.5) pg/ml vs. CSA 1.7 (1.4-4.0) pg/ml, P = 0.02] were higher in ACS than CSA, without a correlation with IMA inflammation. The higher E-selectin, MHC class I and MHC class II-DR on the endothelium and vasa vasorum of IMA from ACS patients suggests a mild, endothelial inflammatory activation in ACS, which can be unrelated to the presence of atherosclerotic coronary lesions. These findings indicated IMA as active vessels in coronary syndromes.
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PMID:Mild inflammatory activation of mammary arteries in patients with acute coronary syndromes. 1844 Nov 95

Sepsis remains the most common cause of death in intensive care units in the USA, with a current estimate of at least 750,000 cases per year, and 215,000 deaths annually. Despite extensive research still we do not quite understand the cellular and molecular mechanisms that are involved in triggering and propagation of septic injury. Endotoxin (lipopolysaccharide from Gram-negative bacteria, or LPS) has been implicated as a major cause of this syndrome. Inflammatory shock as a consequence of LPS release remains a serious clinical concern. In humans, inflammatory responses to LPS result in the release of cytokines and other cell mediators from monocytes and macrophages, which can cause fever, shock, organ failure and death. A number of different approaches have been investigated to try to treat and/or prevent the septic shock associated with infections caused by Gram-negative bacteria, including blockage of one or more of the cytokines induced by LPS. Recently several novel amphipathic compounds have been developed as direct LPS antagonists at the LPS receptor, TLR4. This review article will outline the current knowledge on the TLR4-LPS synthesis and discuss the signaling, in vitro pre-clinical and in vivo clinical evaluation of TLR4 antagonists and their potential use in sepsis and a variety of diseases such as atherosclerosis as well as hepatic and renal malfunction.
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PMID:Discovery and development of toll-like receptor 4 (TLR4) antagonists: a new paradigm for treating sepsis and other diseases. 1849 43

Inflammatory process plays a fundamental role in ischemic coronary artery disease (CAD) in terms of both the etiology of atherosclerosis and the pathophysiology of CAD. In particular, chronic inflammation plays a key role in coronary artery plaque instability and subsequent occlusive thrombosis. It is therefore important to clarify the mechanism underlying the activation of the immune response in the pathogenesis of CAD. Currently 10 toll-like receptors (TLRs) have been reported in mammalian species, and these appear to recognize distinct pathogen-associated molecular patterns controlling innate immune responses. In recent studies, signaling of two forms of human TLR (TLR2 and TLR4) has been shown to be involved in the pathogenesis of CAD, establishing a key link between the progression of coronary atherosclerosis and immune response to both foreign pathogens and endogenously generated inflammatory ligands. A better understanding of TLR signal may provide a novel therapeutic agent for the treatment of CAD. This review summarizes the relationship between the pathogenesis of ischemic coronary artery disease and the human TLR system.
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PMID:Role of Toll like receptor signaling pathway in ischemic coronary artery disease. 1850 89

While the use of nonspecific immunosuppressive drugs has significantly reduced the incidence of acute graft rejection, the benefits of such therapies on chronic rejection and overall long-term graft survival are uncertain. Persistent excessive immunosuppression after immunosuppressive drug treatment is associated with long-term toxicity including increased incidence of cancers, severe infectious complications and metabolic diseases (for example, diabetes, atherosclerosis). One of our team's aims is to identify immunological factors that can predict such toxicities. We have previously demonstrated that CD4T cell cytopenia was correlated with high risk of cancers and infections as well as atherosclerosis in renal transplant recipients. Now, we are investigating the mechanisms involved in CD4T cell cytopenia. We are also exploring how inflammation and cells from the innate immunity influence the complications associated with kidney transplantation. This was performed through the analysis of gene polymorphism on TLR-4, NOD2/CARD15 receptors and IL-6 promoter and correlation with transplantation outcome. We already correlated IL-6 promoter gene polymorphism at position -174 with new-onset diabetes after transplantation in overweight patients. Identification of gene polymorphisms or factors associated with complications after transplantation may help physicians to determine high-risk recipient profiles and optimize pre- and post-transplantation treatment strategies.
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PMID:[Immune monitoring of kidney transplant recipients: can markers predictive of over-immunosuppression be identified?]. 1857 Sep 10

Inflammation and genetics are prominent mechanisms in the pathogenesis of atherosclerosis (AT) and its complications. In this review we discuss the possible impact on AT development of several genetic determinants involved in inflammation, oxidative stress and cytoprotection (IL-6, TNF-alpha, IL-10, CD14, TLR4, MT, HSP70). Genetic polymorphisms of these genes may affect a differential inflammatory response predisposing to AT. However, allelic polymorphisms of genes which increase the risk of AT frequently occur in the general population but, only adequate gene-environment-polymorphism interactions promote the onset of the disease. Zinc deficiency has been suggested as an environmental risk factor for AT. With advancing age, the incidence of zinc deficiency increases for several reasons. Among them, dietary intake, malabsorption and genetic background of inflammatory markers may be involved. A crucial contribution may also be played by increased oxidative stress which may lead to the appearance of dysfunctional proteins, including metallothioneins (MT) that are in turn involved in zinc homeostasis. The detection of candidate genes related to inflammation and promoting AT and their reciprocal influence/interaction with zinc status might allow earlier appropriate dietary interventions in genetically susceptible subjects.
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PMID:Pro-inflammatory genetic background and zinc status in old atherosclerotic subjects. 1861 49

Inflammation is an important event in the development of vascular diseases such as hypertension, atherosclerosis, and restenosis. In addition, the stimulation of Toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) induces the release of critical proinflammatory cytokines that activate potent immune responses. In this study, LPS was found to induce TLR4 expression and increased nitric oxide (NO) production by increasing the expression of inducible nitric oxide synthase (iNOS). Furthermore, LPS was found to induce interleukin (IL)-8 and vascular endothelial growth factor (VEGF) production, as well as intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression. Taken together, these results indicate that LPS induces inflammatory responses in HASMC. Moreover, NOS inhibitor (L-NAME) and anti-TLR 4mAb reduced the LPS-induced NO, IL-8 and VEGF production and ICAM-1 expression. Additionally, TLR4 expression was reduced by NOS inhibitor. Taken together, these results indicate that LPS-induced inflammatory responses are regulated by TLR4 expression and NO production.
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PMID:LPS induces inflammatory responses in human aortic vascular smooth muscle cells via Toll-like receptor 4 expression and nitric oxide production. 1867 2

Fibrinogen has been implicated in atherosclerosis; in part by activating the lipopolysaccharide (LPS) receptor Toll-like receptor 4 (TLR4). The fibrinogen-TLR4 signalling pathway remains uncharacterised. In human macrophages fibrinogen stimulated interleukin (IL)6 expression and ERK (extracellular signal-related kinase) phosphorylation. In HEK293-CD14-MD2 cells expressing TLR4, fibrinogen induced robust phosphorylation of ERK1, p38alpha and JNK and activated transcription factors NFkappaB, Elk-1 and AP-1 (activator protein-1). The net effect of this signalling pathway was a pro-inflammatory response characterised by IL6 and TNFalpha synthesis and increased IL8, matrix metalloproteinase (MMP)1, MMP9, and MCP-1 promoter activity. Two common TLR4 mutations, D299G and T399I, render the receptor LPS hyporesponsive. The effect of fibrinogen on polymorphic variant TLR4s was markedly different; enhancing activation of kinases, transcription factors, cytokine synthesis and promoter activity. This study indicates that fibrinogen activates TLR4, explaining how fibrinogen promotes inflammatory protein expression.
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PMID:Functional Toll-like receptor 4 mutations modulate the response to fibrinogen. 1869 Mar 51

Cardiovascular diseases are the human diseases with the highest death rate and atherosclerosis is one of the major underlying causes of cardiovascular diseases. Inflammatory and innate immune mechanisms, employing monocytes, innate receptors, innate cytokines, or chemokines are suggested to be involved in atherogenesis. Among the inflammatory pathways the cytokines are central players. Plasma levels of cytokines and related proteins, such as CRP, have been investigated in cardiovascular patients, tissue mRNA expression was analyzed and correlations to vascular diseases established. Consistent with these findings the generation of cytokine-deficient animals has provided direct evidence for a role of cytokines in atherosclerosis. In vitro cell culture experiments further support the suggestion that cytokines and other innate mechanisms contribute to atherogenesis. Among the initiation pathways of atherogenesis are innate mechanisms, such as toll-like-receptors (TLRs), including the endotoxin receptor TLR4. On the other hand, innate cytokines, such as IL-1 or TNF, or even autoimmune triggers may activate the cells. Cytokines potently activate multiple functions relevant to maintain or spoil homeostasis within the vessel wall. Vascular cells, not least smooth muscle cells, can actively contribute to the inflammatory cytokine-dependent network in the blood vessel wall by: (i) production of cytokines; (ii) response to these potent cell activators; and (iii) cytokine-mediated interaction with invading cells, such as monocytes, T-cells, or mast cells. Activation of these pathways results in accumulation of cells and increased LDL- and ECM-deposition which may serve as an 'immunovascular memory' resulting in an ever-growing response to subsequent invasions. Thus, vascular cells may potently contribute to the inflammatory pathways involved in development and acceleration of atherosclerosis.
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PMID:Vascular cells contribute to atherosclerosis by cytokine- and innate-immunity-related inflammatory mechanisms. 1871 24

The Toll-like receptor 4 is a key mediator of the innate immune response. Besides its main ligand, the Gram-negative bacterial lipopolysaccharides, other molecules such as heat-shock protein 60, oxidized low density lipoprotein and fibronectin can also bind to the receptor. Activation of the Toll-like receptor induces the production of proinflammatory cytokines. There is increasing evidence showing that the Toll-like receptor 4 plays a role not only in the immune reaction against infectious agents but also in chronic non-infectious inflammatory diseases, such as atherosclerosis, diabetes mellitus and inflammatory bowel disease. This review briefly summarizes recent knowledge on the Toll-like receptor 4, its common co-segregation polymorphisms and the impact of these polymorphisms on various human diseases.
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PMID:[Polymorphisms of the Toll-like receptor 4 gene and their potential role in infectious diseases and chronic inflammatory disorders]. 1880 65


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