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)

An effective host response to infection or tissue damage requires focal accumulation of leukocytes. Leukocyte adhesion to the vessel wall, a key step in this process, depends on the ordered expression of specific endothelial cell surface molecules. The endothelial molecules that support adhesion include selectins that recognize leukocyte cell surface glycoconjugates as well as members of the immunoglobulin superfamily that interact with leukocyte integrins. Although inflammation can occur with minimal damage to the vessel wall and surrounding tissues, control mechanisms sometimes appear to fail, and the inflammatory response itself becomes a significant clinical problem. In this review, we discuss endothelial-leukocyte adhesion molecules with particular emphasis on their expression and function in human disease. Pathophysiological processes presented include atherosclerosis, ischemia-reperfusion injury, acute lung injury, rheumatoid arthritis, and graft rejection. A more detailed description of the discovery and characterization of the key molecules appears in the antecedent article entitled "Endothelial-Leukocyte Adhesion Molecules".
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PMID:Endothelial-leukocyte adhesion molecules in human disease. 751 20

The aim of this review is to summarize the current concepts concerning the active role of the endothelium in the pathogenesis of atherosclerosis. Activated endothelium may promote the adhesion of monocytes and their transmigration into the intima. The coordinated expression of adhesion molecules of the selectin, integrin or immunoglobulin superfamily on the surface of endothelial cells and of monocytes modulates these events. The role of lipoproteins and their oxidative derivatives as well as that of selected cytokines and platelet activated factor in initiating changes on the endothelial cell surface has been investigated: these events are associated with an increased endothelial permeability to lipids and lipoproteins with their accumulation in the subendothelium. Once migrated into the intima, monocytes undergo morphological and functional modifications leading to the generation of a polypeptide mediator network which is instrumental in the migration, differentiation and proliferation of smooth muscle cells. Mediators produced by macrophages infiltrating the atherosclerotic plaque and by the endothelium may render the surface of the endothelial cells thrombogenic thus favoring thrombotic occlusion. In conclusion, the most recent studies suggest that the endothelium plays an active role in the pathogenesis of atherosclerosis.
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PMID:[Functional changes of the endothelium and atherosclerotic process]. 772 4

Advanced glycation end products (AGEs) form by the interaction of aldoses with proteins and the subsequent molecular rearrangements of the covalently linked sugars, eventuating in a diverse group of fluorescent compounds of yellow-brown color. This heterogeneous class of nonenzymatically glycated proteins or lipids is found in the plasma and accumulates in the vessel wall and tissues even in normal aging. As a consequence of hyperglycemia, AGE formation and deposition are much enhanced in diabetes, in which their presence has been linked to secondary complications, especially microvascular disease. This review summarizes the cellular interactions of AGEs and describes the central role of a novel receptor for AGE (RAGE). RAGE, an immunoglobulin superfamily member, mediates the binding of AGEs to endothelial cells and mononuclear phagocytes, interacts with a lactoferrin-like polypeptide that also binds AGEs, and appears to activate intracellular signal transduction mechanisms consequent to its interaction with the glycated ligand. RAGE is expressed by ECs, mononuclear phagocytes, smooth muscle cells, mesangial cells, and neurons, indicating a potential role in the regulation of their properties in homeostasis and/or their dysfunction in the development of diabetic complications. Since AGEs have been shown to generate reactive oxygen intermediates, tethering of AGEs to the cell surface by their receptors focuses oxidant stress on cellular targets, resulting in changes in gene expression and the cellular phenotype. The discovery of RAGE and development of reagents to block its interaction with AGEs should provide insights into the role of this ligand-receptor interaction in the pathogenesis of diabetic complications and, potentially, atherosclerosis.
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PMID:Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. 791

To date, six families of cell adhesion molecules are known. These are cell surface receptors that mediate adhesion of cells to each other or to components of the extracellular matrix and include integrins, selectins, the immunoglobulin superfamily, cadherins, proteoglycans and mucins. These cell adhesion molecules play a key role in cell-cell interaction (such as among endothelium, monocytes, smooth muscle cells and platelets) and cell-extracellular matrix interaction (such as between leukocytes, platelets or fibroblasts and the extracellular matrix). The importance of these interactions has recently been demonstrated in clinical trials with the use of an antibody fragment directed against the platelet alpha IIb beta IIIa integrin, with reduction of arterial thrombosis and restenosis after percutaneous coronary interventions. A fundamental role for cell adhesion molecules has been suggested for several other relevant disease processes, including atherosclerosis, acute coronary syndromes, reperfusion injury and allograft vasculopathy. This review focuses on providing the clinically relevant biology of these families of adhesion molecules, setting the foundation for delineation of their emerging role in cardiovascular therapeutics.
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PMID:Cell adhesion molecules in coronary artery disease. 796 3

An understanding of inflammatory responses is important in a wide variety of tissue engineering applications. This review describes the current understanding of a central aspect of inflammatory responses, the adhesion of leucocytes to blood vessel walls prior to their emigration into tissues. These highly specific adhesive interactions are mediated by three main families of receptors: the selectins, integrins, and members of the immunoglobulin superfamily. Under flow conditions, the various receptors make distinct contributions to a multistep process of adhesion in which leucocytes roll, adhere firmly, and eventually transmigrate. Two examples in which these principles are important in tissue engineering research, lymphocyte adherence in transplant rejection and monocyte adherence in atherosclerosis, are discussed in the last part of the paper.
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PMID:Leucocyte adhesion under flow conditions: principles important in tissue engineering. 874 31

Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules and engages diverse ligands relevant to distinct pathological processes. One class of RAGE ligands includes glycoxidation products, termed advanced glycation end products, which occur in diabetes, at sites of oxidant stress in tissues, and in renal failure and amyloidoses. RAGE also functions as a signal transduction receptor for amyloid beta peptide, known to accumulate in Alzheimer disease in both affected brain parenchyma and cerebral vasculature. Interaction of RAGE with these ligands enhances receptor expression and initiates a positive feedback loop whereby receptor occupancy triggers increased RAGE expression, thereby perpetuating another wave of cellular activation. Sustained expression of RAGE by critical target cells, including endothelium, smooth muscle cells, mononuclear phagocytes, and neurons, in proximity to these ligands, sets the stage for chronic cellular activation and tissue damage. In a model of accelerated atherosclerosis associated with diabetes in genetically manipulated mice, blockade of cell surface RAGE by infusion of a soluble, truncated form of the receptor completely suppressed enhanced formation of vascular lesions. Amelioration of atherosclerosis in these diabetic/atherosclerotic animals by soluble RAGE occurred in the absence of changes in plasma lipids or glycemia, emphasizing the contribution of a lipid- and glycemia-independent mechanism(s) to atherogenesis, which we postulate to be interaction of RAGE with its ligands. Future studies using mice in which RAGE expression has been genetically manipulated and with selective low molecular weight RAGE inhibitors will be required to definitively assign a critical role for RAGE activation in diabetic vasculopathy. However, sustained receptor expression in a microenvironment with a plethora of ligand makes possible prolonged receptor stimulation, suggesting that interaction of cellular RAGE with its ligands could be a factor contributing to a range of important chronic disorders.
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PMID:Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. 1008 70

This review discusses three stages in the life history of an atheroma: initiation, progression and complication. Recruitment of mononuclear leucocytes to the intima characterizes initiation of the atherosclerotic lesion. Specific adhesion molecules expressed on the surface of vascular endothelial cells mediate leucocyte adhesion: the selectins and members of the immunoglobulin superfamily such as vascular cell adhesion molecule-1 (VCAM-1). Once adherent, the leucocytes enter the artery wall directed by chemoattractant chemokines such as macrophage chemoattractant protein-1 (MCP-1). Modified lipoproteins contain oxidized phospholipids which can elicit expression of adhesion molecule and cytokines implicated in early atherogenesis. Progression of atheroma involves accumulation of smooth muscle cells which elaborate extracellular matrix macromolecules. These processes appear to result from an eventual net positive balance of growth stimulatory versus growth inhibitory stimuli, including proteins (cytokines and growth factors) and small molecules (e.g. prostanoids and nitric oxide). The clinically important complications of atheroma usually involve thrombosis. Arterial stenoses by themselves seldom cause acute unstable angina or acute myocardial infarction. Indeed, sizeable atheroma may remain silent for decades or produce only stable symptoms such as angina pectoris precipitated by increased demand. Recent research has furnished new insight into the molecular mechanisms that cause transition from the chronic to the acute phase of atherosclerosis. Thrombus formation usually occurs because of a physical disruption of atherosclerotic plaque. The majority of coronary thromboses result from a rupture of the plaque's protective fibrous cap, which permits contact between blood and the highly thrombogenic material located in the lesion's lipid core, e.g. tissue factor. Interstitial collagen accounts for most of the tensile strength of the plaque's fibrous cap. The amount of collagen in the lesion's fibrous cap depends upon its rate of biosynthesis stimulated by factors released from platelets (e.g. transforming growth factor beta or platelet-derived growth factor), but inhibited by gamma interferon, a product of activated T cells found in plaques. Degradation by specialized enzymes (matrix metalloproteinases) also influences the level of collagen in the plaque's fibrous cap. Such studies illustrate how the application of cellular and molecular approaches has fostered a deeper understanding of the pathogenesis of atherosclerosis. This increased knowledge of the basic mechanisms enables us to understand how current therapies for atherosclerosis may act. Moreover, the insights derived from recent scientific advances should aid the discovery of new therapeutic targets that would stimulate development of novel treatments. Such new treatments could further reduce the considerable burden of morbidity and mortality due to this modern scourge, and reduce reliance on costly technologies that address the symptoms rather than the cause of atherosclerosis.
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PMID:Changing concepts of atherogenesis. 1076 52

Receptor for advanced glycation end products (RAGE) is a multiligand member of the immunoglobulin superfamily of cell surface molecules whose repertoire of ligands includes advanced glycation end products (AGEs), amyloid fibrils, amphoterins and S100/calgranulins. The overlapping distribution of these ligands and cells overexpressing RAGE results in sustained receptor expression which is magnified via the apparent capacity of ligands to upregulate the receptor. We hypothesize that RAGE-ligand interaction is a propagation factor in a range of chronic disorders, based on the enhanced accumulation of the ligands in diseased tissues. For example, increased levels of AGEs in diabetes and renal insufficiency, amyloid fibrils in Alzheimer's disease brain, amphoterin in tumors and S100/calgranulins at sites of inflammation have been identified. The engagement of RAGE by its ligands can be considered the 'first hit' in a two-stage model, in which the second phase of cellular perturbation is mediated by superimposed accumulation of modified lipoproteins (in atherosclerosis), invading bacterial pathogens, ischemic stress and other factors. Taken together, these 'two hits' eventuate in a cellular response with a propensity towards tissue destruction rather than resolution of the offending pathogenic stimulus. Experimental data are cited regarding this hypothesis, though further studies will be required, especially with selective low molecular weight inhibitors of RAGE and RAGE knockout mice, to obtain additional proof in support of our concept.
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PMID:The biology of the receptor for advanced glycation end products and its ligands. 1110 54

Adhesion of circulating cells to the vascular endothelium is an early step in the development of atherosclerosis. Diabetic patients have a 2-4 fold increased risk for the development of atherosclerosis. Expression of adhesion molecules is increased in diabetes. These molecules may contribute to accelerated atherosclerosis in diabetes. Three main groups of adhesion molecules have been identified: integrins, selectins and members of the immunoglobulin superfamily. The modulation of expression and activity of adhesion molecules may play an important role in the prevention and treatment of atherosclerosis. This article summarises the characteristics and the role of these molecules in atherosclerosis and diabetes.
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PMID:[The role of adhesion molecules in atherosclerosis and diabetes mellitus]. 1112 80

A variety of recently discovered glycoproteins have been implicated in cell-cell interactions that are critical for normal hemostasis, immune surveillance, and vascular wall integrity. These cell adhesion molecules (CAM) are known to mediate blood cell (leukocyte, platelet)-endothelial cell interactions that can occur in all segments of the microvasculature under certain physiological (eg, hemostasis) and pathological (eg, inflammation) conditions. The multistep process of leukocyte recruitment illustrates how the coordinated and regulated expression of structurally and functionally distinct families of CAM can elicit a highly reproducible vascular response to inflammation. Selectins mediate the initial, low-affinity leukocyte-endothelial cell interaction that is manifested as leukocyte rolling. This transient binding results in further leukocyte activation and subsequent firm adhesion and transendothelial migration of leukocytes, both of which are mediated by interactions between members of the integrin and immunoglobulin superfamily of CAM. This CAM-regulated process of leukocyte recruitment often results in endothelial cell dysfunction, which can be manifested as either impaired endothelium-dependent vasorelaxation in arterioles, excess fluid filtration in capillaries, and enhanced protein extravasation in venules. Consequently, CAM have been implicated in a variety of vascular disorders (eg, ischemia/reperfusion, atherosclerosis, allograft dysfunction, and vasculitis) and an enhanced expression of these CAM has been invoked to explain the exaggerated microvascular dysfunction associated with some of the risk factors (hypertension, hypercholesterolemia, diabetes) for cardiovascular disease. Monoclonal antibodies and genetically engineered mice have proven to be valuable tools for defining the contribution of CAM to disease progression and provide hope for new diagnostic and therapeutic strategies for cardiovascular diseases.
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PMID:Adhesion molecules and their role in vascular disease. 1141 65


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