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)

Complement (C) activation is thought to contribute to the initiation and progression of atherosclerosis. Proliferation of smooth muscle cells plays an important role in atherosclerotic plaque formation. Our aim was to investigate the suitability of the rat aortic smooth muscle cell line A7r5 as an in vitro model to study C-induced events in smooth muscle cells. A7r5 cells abundantly expressed membrane bound C-regulators (CReg) Crry and CD59 as assessed by flow-cytometry, but no DAF or MCP was detected. Using RT-PCR in addition to Crry and CD59, also mRNA for rat DAF but not for MCP was detected. Flow-cytometry of cells removed by EDTA instead of trypsin demonstrated that A7r5 did express cell surface DAF. Upon prolonged culturing under either logarithmic growing conditions or under conditions where cells were kept over-confluent, two different sub cell lines were obtained, one which had lost the expression of CD59, while the other showed increased expression of DAF and Crry. The change in expression of these CReg resulted in a change in C-susceptibility. Incubation of the A7r5 cells with human serum induced membrane attack complex dependent proliferation. Transfection with human CD59 efficiently protected the cells from C-mediated killing and C-induced cell proliferation. Our results show that A7r5 cells can be used as an in vitro model for C-induced events, but care has to be taken to use the cells at an early stage of passaging as they readily change their phenotype.
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PMID:Characterisation of the complement susceptibility of the rat aortic smooth muscle cell line A7r5. 1651 69

The extracellular fluid of the intima is rich in lipid-poor species of high density lipoproteins (HDL) that promote efficient efflux of cholesterol from macrophages. Yet, during atherogenesis, cholesterol accumulates in macrophages, and foam cells are formed. We have studied proteolytic modification of HDL by mast cell proteases as a potential mechanism of reduced cholesterol efflux from foam cells. Mast cells are present in human atherosclerotic lesions and, when activated, they expel cytoplasmic granules that are filled with heparin proteoglycans and two neutral proteases, chymase and tryptase. Both proteases were found to specifically deplete in vitro the apoA-I-containing prebeta-migrating HDL (prebeta-HDL) and other lipid-poor HDL particles that contain only apoA-IV or apoE. These losses led to inhibition of the high-affinity component of cholesterol efflux from macrophage foam cells facilitated by the ATP-binding cassette transporter A1 (ABCA1). In contrast, the diffusional component of efflux promoted by alpha-HDL particles was not changed after proteolysis. Mast cell proteases are providing new insights into the role of extracellular proteolysis of HDL as an inhibiting principle of the initial steps of reverse cholesterol transport in the atherosclerotic intima, where many types of protease-secreting cells are present.
Atherosclerosis 2006 Nov
PMID:Mast cell proteases: physiological tools to study functional significance of high density lipoproteins in the initiation of reverse cholesterol transport. 1653 Feb 2

Excessive or misplaced activation of leukocytes causes host tissue damage which has been implicated in diseases such as atherosclerosis and chronic inflammation. This may arise via either the generation of oxidants such as hypochlorous acid (HOCl) by the heme enzyme myeloperoxidase, the action of released enzymes including lysozyme and proteases, or a combination of these two activities. Thus, oxidant-mediated inactivation of protease inhibitors that modulate tissue proteolysis by the released enzymes may exacerbate protease-induced degradation of host tissue. The role of myeloperoxidase-derived oxidants, such as HOCl, in the inactivation of Kunitz-type inhibitors and lysozyme is not well-characterized and is the subject of the current study. Exposure of both trypsin inhibitor and lysozyme to low molar excesses of HOCl compared to protein is shown to result in loss of function. With trypsin inhibitor, this loss of activity is associated with the selective oxidation of Trp, Tyr, and His residues, which results in protein unfolding and the disruption of complex formation with active trypsin. Oxidation of Met residues, a major target for HOCl, or the active site Arg, does not appear to play a key role in this loss of activity. In contrast, with lysozyme, oxidation of Met residues to Met sulfoxide appears to be the major process resulting in loss of enzyme activity. With both proteins, inactivation occurs in a time-dependent manner, consistent with both direct oxidation by HOCl and secondary reactions of protein chloramines formed from amine groups (e.g., from Lys and His) playing a role in loss of activity.
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PMID:Inactivation of protease inhibitors and lysozyme by hypochlorous acid: role of side-chain oxidation and protein unfolding in loss of biological function. 1653 25

Alkaline sphingomyelinase (alk-SMase) is present in the intestinal tract and additionally human bile. It hydrolyses sphingomyelin in both intestinal lumen and the mucosal membrane in a specific bile salt dependent manner. The enzyme was discovered 36 years ago but got real attention only in the last decade, when sphingomyelin metabolism was realized to be a source of multiple lipid messengers, and when dietary sphingomyelin was found to inhibit colonic tumorigenesis in animals. The enzyme shares no structural similarity with other SMases and belongs to the nucleotide pyrophosphatase/phosphodiesterase family. The enzyme is of specific properties, such as bile salt dependency, trypsin resistance, high stability, and tissue specific expression. In the colon, the enzyme may play antiproliferative and antiinflammatory roles through generating ceramide, reducing the formation of lysophosphatidic acid, and inactivating platelet-activating factor. The enzyme is down regulated in human long-standing ulcerative colitis and colonic adenocarcinoma, and mutation of the enzyme has been found in colon cancer cells. In the small intestine, alk-SMase is the key enzyme for sphingomyelin digestion. The hydrolysis of sphingomyelin may affect the cholesterol uptake and have impact on sphingomyelin levels in plasma lipoproteins. The review summarizes the new information of alk-SMase from biochemical, cell and molecular biological studies in the last decade and evaluates its potential implications in development of colon cancer, inflammatory bowel diseases, and atherosclerosis.
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PMID:Alkaline sphingomyelinase: an old enzyme with novel implications. 1663 5

Serine proteinases (trypsin and chymotrypsin) cause destruction of apolipoprotein B-100 on the surface of human blood LDL. Incubation of LDL with these enzymes increases the mean size of LDL particles. Proteolysis of apolipoprotein B-100 induces changes in surface structure, destabilizes LDL particles, and reduces their association resistance. Presumably, this proteolytic modification of LDL with subsequent association of these particles plays an important role in accumulation of cholesterol in the vascular wall and in the development of early stages of atherosclerosis.
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PMID:Proteolysis of apoprotein B-100 impairs its topography on LDL surface and reduces LDL association resistance. 1675 14

Leukocyte recruitment and the expression of pro-inflammatory cytokines are prevalent characteristics of early atherogenesis. Recently, several inflammatory mediators have been linked to atheroma formation and inflammatory pathways have been shown to promote thrombosis. The discovery of mast cells, activated T lymphocytes and macrophages in atherosclerotic lesions, the detection of human leukocyte antigen class II expression, and the finding of local secretion of several cytokines all suggest the involvement of immune and inflammatory mechanisms in the pathogenesis of atherosclerosis. Recent research suggests activation of protease activated receptors (PAR) on the surface of endothelial cells may play a role in general mechanisms of inflammation. In previous studies, our laboratory has demonstrated that thrombin (which activates PAR-1) and tryptase (which activates PAR-2) stimulation of endothelial cells results in activation of calcium-independent phospholipase A(2) (iPLA(2)). iPLA(2) plays a critical role in the synthesis of membrane phospholipid-derived inflammatory mediators such as arachidonic acid, platelet activating factor (PAF), and prostaglandins, all demonstrated to be central in both the initiation and propagation of the inflammatory response. Activation of iPLA(2) results in release of choline lysophospholipids from endothelial cells, these metabolites may contribute to the initiation of ventricular arrhythmias following myocardial ischemia as a direct result of incorporation into the myocyte sarcolemma. This biochemical event represents a direct link between occlusion of a coronary vessel and the nearly immediate initiation of arrhythmogenesis often seen in myocardial ischemia.
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PMID:The therapeutic potential of phospholipase A2 inhibitors in cardiovascular disease. 1726 51

Atherosclerotic plaque formation is a dynamic process involving repeated injury and inflammation of the endothelium. We have demonstrated previously that thrombin and tryptase stimulation of human coronary artery endothelial cells (HCAEC) leads to increased phospholipase A(2) (PLA(2)) activity and generation of membrane phospholipid derived inflammatory metabolites, including eicosanoids and platelet activating factor. Thus, our hypothesis is that selective PLA(2) inhibitors have therapeutic potential as anti-inflammatory agents. Stimulation of confluent HCAEC monolayers with thrombin or tryptase resulted in a concentration and time-dependent increase in both prostaglandin E(2) (PGE(2)) and prostacyclin (PGI(2)) production. Pretreatment with PX-18 to inhibit secretory PLA(2) or BEL to inhibit calcium-independent PLA(2) prior to thrombin or tryptase stimulation resulted in a significant inhibition of both PGI(2) and PGE(2) release. However, pretreatment with methyl arachidonyl fluorophosphonate (MAFP), a widely used inhibitor of cytosolic PLA(2) isoforms, resulted in a significant potentiation of both thrombin and tryptase stimulated PGI(2) and PGE(2) release as a consequence of increased free arachidonic acid production. We conclude that the use of selective PLA(2) inhibitors may be of therapeutic benefit in the development and progression of atherosclerosis, however, the development of such an agent requires rigorous screening.
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PMID:Prostaglandin production in human coronary artery endothelial cells is modulated differentially by selective phospholipase A(2) inhibitors. 1737 79

Our understanding of the relationship between the proatherogenic activities of arterial mast cells (MCs) and the development of atherosclerotic lesions is advancing. Atherosclerosis is a chronic inflammatory disease in which cholesterol and other lipids of circulating low-density lipoprotein (LDL) particles accumulate both extracellularly and intracellularly in the innermost layer of the arterial wall, the intima. One prerequisite for the proatherogenic activity of the LDL particles is their retention and proteolytic modification within the extracellular matrix of the intima. Experimental studies with activated chymase-secreting MCs have provided us fundamental insights into the molecular mechanisms of these processes. High-density lipoprotein (HDL) particles, again, remove cholesterol from the intracellular stores and carry it back to the circulation. MC chymase and tryptase actively degrade HDL and thus generate functionally defective particles that are unable to initiate cholesterol efflux from the arterial wall. In advanced atherosclerotic plaques, the accumulated lipids are separated from the circulation by a collagenous cap. By inducing apoptosis of endothelial cells (ECs), subendothelial MCs may induce detachment of ECs from the cap (plaque erosion). Moreover, MCs may weaken the cap if they disturb local collagen turnover by inducing apoptosis of the collagen-secreting smooth muscle cells or when they promote collagen degradation by activating matrix metalloproteinases. Plaques with a weak cap are vulnerable to rupture. The exposed subendothelial tissue at eroded and ruptured sites of plaques triggers local development of a platelet-rich thrombus. As regulators of the collagen-induced platelet activation and fibrin formation/fibrinolysis, the MCs may retard or accelerate the growth of the plaque-associated thrombus and ultimately participate in the wound-healing response of the injured plaque. We propose that by promoting cholesterol accumulation and plaque vulnerability and by locally regulating hemostasis, MCs in atherosclerotic lesions have the potential to contribute to the clinical outcomes of atherosclerosis, such as myocardial infarction and stroke.
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PMID:Mast cells: multipotent local effector cells in atherothrombosis. 1749 55

Cardiac mast cells proliferate in cardiovascular diseases. In myocardial ischemia, mast cell mediators contribute to coronary vasoconstriction, arrhythmias, leukocyte recruitment, and tissue injury and repair. Arrhythmic dysfunction, coronary vasoconstriction, and contractile failure are also characteristic of cardiac anaphylaxis. In coronary atherosclerosis, mast cell mediators facilitate cholesterol accumulation and plaque destabilization. In cardiac failure, mast cell chymase causes myocyte apoptosis and fibroblast proliferation, leading to ventricular dysfunction. Chymase and tryptase also contribute to fibrosis in cardiomyopathies and myocarditis. In addition, mast cell tumor necrosis factor-alpha promotes myocardial remodeling. Cardiac remodeling and hypertrophy in end-stage hypertension are also induced by mast cell mediators and proteases. We recently discovered that cardiac mast cells contain and release renin, which initiates local angiotensin formation. Angiotensin causes coronary vasoconstriction, arrhythmias, fibrosis, apoptosis, and endothelin release, all demonstrated mechanisms of mast-cell-associated cardiac disease. The effects of angiotensin are further amplified by the release of norepinephrine from cardiac sympathetic nerves. Our discovery of renin in cardiac mast cells and its release in pathophysiological conditions uncovers an important new pathway in the development of mast-cell-associated heart diseases. Several steps in this novel pathway may constitute future therapeutic targets.
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PMID:Renin: at the heart of the mast cell. 1749 56

Activation of PAR-2 in the vasculature affects vascular tone and adhesion of leukocytes to the endothelium. Since adhesion of leukocytes is increased following vascular injury and is important in determining the extent of neointima formation, we hypothesised that mice lacking PAR-2 may have reduced neointima formation following vascular injury. PAR-2 activating peptides and trypsin induced endothelium-dependent relaxation of mouse carotid artery which was absent in the knockout mouse. Lack of a PAR-2 receptor did not affect lymphocyte adhesion under basal conditions, but reduced the contractile response produced by lymphocytes. Twenty-eight days after denuding injury, vessel contraction to lymphocytes was reduced in both strains while lymphocyte adhesion was significantly greater in PAR-2(+/+) mice compared to the PAR-2 knockout mice. Neointimal area was markedly reduced in the PAR-2 knockout mouse. Our data show that PAR-2 modulates inflammatory cell adhesion when stimulated and in mice lacking the PAR-2 receptor, adhesion to injured vessels is reduced with a consequent reduction in neointima formation.
Atherosclerosis 2008 May
PMID:PAR-2 mediates increased inflammatory cell adhesion and neointima formation following vascular injury in the mouse. 1799 73


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