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)

Mast cells have been assigned a role in neovascularization. Therefore, we examined the deep regions of human coronary atheromas, the areas known to be prone to neovascularization, for the presence of mast cells. Specimens of atherosclerotic human coronary intima from 37 autopsy cases with ages of 24-84 years were stained with elastica-van Gieson to detect atheroma formation and with monoclonal antibody against von Willebrand factor to detect neovascularization. Mast cells were detected by staining the atheromas with monoclonal antibodies against the two major proteases of mast cells, tryptase and chymase. Of the 24 coronary atheromas found, 13 contained mast cells in the deep regions. All these 13 deep regions also displayed neovascularization, and the number of microvessels and the number of mast cells around the microvessels correlated strongly with the size of the atheroma. On the other hand, of the 11 deep regions lacking mast cells, only one displayed neovascularization. In the neovascularized areas of the coronary atheromas, the mast cells were in close proximity to the microvessels. All the mast cells contained tryptase, and some of them chymase, both known for their angiogenic and matrix-degrading potential. In light microscopic studies, degranulated mast cells were observed indicating activation of these cells, with release of tryptase and chymase. The selective localization of activated mast cells containing angiogenic factors around newly formed microvessels in human coronary atheromas suggests that mast cells play a role in the neovascularization of these lesions. Moreover, mast cells may also, by virtue of their neutral proteases, injure the microvessels, and thereby produce intraplaque hemorrhages and, ultimately, unstable lesions.
Atherosclerosis 1996 Jun
PMID:Mast cells accompany microvessels in human coronary atheromas: implications for intimal neovascularization and hemorrhage. 878 43

This study examines the role of L-selectin in monocyte adhesion to arterial endothelium, a key pathogenic event of atherosclerosis. Using a nonstatic (rotation) adhesion assay, we observed that monocyte binding to bovine aortic endothelium at 4 degrees C increased four to nine times upon endothelium activation with tumor necrosis factor (TNF)-alpha. mAb-blocking experiments demonstrated that L-selectin mediates a major part (64 +/- 18%) of monocyte attachment. Videomicroscopy experiments performed under flow indicated that monocytes abruptly halted on 8-h TNF-alpha-activated aortic endothelium, approximately 80% of monocyte attachment being mediated by L-selectin. Flow cytometric studies with a L-selectin/IgM heavy chain chimeric protein showed calcium-dependent L-selectin binding to cytokine-activated and, unexpectedly, unactivated aortic cells. Soluble L-selectin binding was completely inhibited by anti-L-selectin mAb or by aortic cell exposure to trypsin. Experiments with cycloheximide, chlorate, or neuraminidase showed that protein synthesis and sulfate groups, but not sialic acid residues, were essential for L-selectin counterreceptor function. Moreover, heparin lyases partially inhibited soluble L-selectin binding to cytokine-activated aortic cells, whereas a stronger inhibition was seen with unstimulated endothelial cells, suggesting that cytokine activation could induce the expression of additional ligand(s) for L-selectin, distinct from heparan sulfate proteoglycans. Under flow, endothelial cell treatment with heparinase inhibited by approximately 80% monocyte attachment to TNF-alpha-activated aortic endothelium, indicating a major role for heparan sulfate proteoglycans in monocyte-endothelial interactions. Thus, L-selectin mediates monocyte attachment to activated aortic endothelium, and heparan sulfate proteoglycans serve as arterial ligands for monocyte L-selectin.
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PMID:Monocyte adhesion to activated aortic endothelium: role of L-selectin and heparan sulfate proteoglycans. 904 58

In the last decade, new information was achieved on mast cells (MC). Their origin is assumed to be different from that of the basophils. There are two types of MC with differences in structure, distribution and function: conjunctival and mucosal. MCs are among the most important cells in the development of allergic inflammation through the cytokines and mediators released on the activation of the surface receptors (high-affinity receptors for IgE: Fc epsilon R1). The cytokines released by MCs, e.g., interleukin 5 (IL5), IL8, are chemoattractants for eosinophils and neutrophils, respectively. The two types of mediators released by MC-those preformed, such as histamine, tryptase, serotonin, and the newly-synthetized ones, such as prostaglandin D2 (PGD2), leukotrienes C4 (LTD4), D4 (LTD4), E4 (LTE4), induce vasodilatation, bronchoconstriction, cellular chemotaxis, increase vascular permeability. The involvement of MC in many human diseases was shown within in vivo and in vitro studies (in allergy, lung fibrosis, atherosclerosis, carcinogenesis, etc.).
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PMID:Mast cells as potent inflammatory cells. 916 16

Immunohistochemical staining for mast cell tryptase and chymase was used to examine the distribution, activation, and tryptase/chymase phenotype of mast cells (MCs) in 250 samples of atherosclerotic lesions (type I to VI) of human carotid arteries. Dual immunolocalization and histochemical techniques were used to identify the associations of MCs with macrophages, smooth muscle cells, and extracellular matrix components. Whereas normal carotid arteries contained very few MCs within the intima, atherosclerotic lesions showed increased MC numbers with variable focal accumulations. MCs were identifiable from the earliest stages of atherosclerosis, and especially at the shoulder regions of the fully formed atheroma. They were observed in close association with macrophages (HAM56 positive) and extracellular lipid, as well as at sites of foam cell formation. MCs and diffuse tryptase staining were also evident within sites of new calcification and around small calcified deposits. Extensive MC activation/degranulation, as judged by diffuse extracellular tryptase staining, was a common feature of the advanced atherosclerotic plaques complicated by fissure, haemorrhage, and thrombus formation. Moreover, such sites of extracellular MC tryptase were often associated with localized oedema and disruption of the stromal matrix. MCs which contained both tryptase and chymase (the MCTC phenotype) represented approximately 80-95 per cent of all MCs. These studies are the first to demonstrate significant numbers and focal accumulations of MCs in all developmental stages of atherosclerotic carotid arteries. Since MCs contain or express a variety of potent mediators, their release could profoundly influence the development and pathological complications of atherosclerotic plaques.
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PMID:Mast cell distribution, activation, and phenotype in atherosclerotic lesions of human carotid arteries. 922 50

Arterial unesterified cholesterol, phospholipid particles have been isolated from atherosclerotic lesions and characterized. However, the role of these 'liposomes' in macrophage foam cell formation is unclear. Recently, LDL, after trypsin and cholesteryl esterase treatment (T/CE LDL), was shown to have physical properties similar to the unesterified cholesterol, phospholipid particles isolated from atherosclerotic lesions. Yet, when mouse peritoneal macrophages were incubated with these model particles in culture medium (DMEM and 5% LPDS), only an insignificant accumulation of cellular cholesteryl esters was observed. Previously, we demonstrated that complex formation between unesterified cholesterol, phosphatidylcholine liposomes and cupric sulfate-oxidized LDL dramatically enhances the ability of the liposomes to augment cellular cholesterol accretion (Greenspan P, Yu H, Mao F, Gutman RL. J Lipid Res 1997;38:101-109). When T/CE LDL, another cholesterol-rich phospholipid particle, was substituted for unesterified cholesterol phosphatidylcholine liposomes in our complex, mouse peritoneal macrophages accumulated a significant amount of both cellular unesterifed cholesterol (61 microg/mg cell protein) and cholesteryl esters (76 microg/mg cell protein) after 48 h of incubation. These results demonstrate again that the interaction of two cholesterol-bearing particles (T/CE LDL and oxidized LDL), which individually can not promote significant cholesterol accumulation in cells, will, when combined, produce macrophage foam cells.
Atherosclerosis 1998 Sep
PMID:Cholesteryl esterase-treated LDL augments oxidized LDL-mediated cholesteryl ester deposition in mouse peritoneal macrophages. 973 13

Locally formed angiotensin II (Ang II) and mast cells may participate in the development of atherosclerosis. Chymase, which originates from mast cells, is the major Ang II-forming enzyme in the human heart and aorta in vitro. The aim of the present study was to investigate aortic Ang II-forming activity (AIIFA) and the histochemical localization of each Ang II-forming enzyme in the atheromatous human aorta. Specimens of normal (n=9), atherosclerotic (n=8), and aneurysmal (n=6) human aortas were obtained at autopsy or cardiovascular surgery from 23 subjects (16 men, 7 women). The total, angiotensin-converting enzyme (ACE)-dependent, and chymase-dependent AIIFAs in aortic specimens were determined. The histologic and cellular localization of chymase and ACE were determined by immunocytochemistry. Total AIIFA was significantly higher in atherosclerotic and aneurysmal lesions than in normal aortas. Most of AIIFA in the human aorta in vitro was chymase-dependent in both normal (82%) and atherosclerotic aortas (90%). Immunocytochemical staining of the corresponding aortic sections with antichymase, antitryptase or anti-ACE antibodies showed that chymase-positive mast cells were located in the tunica adventitia of normal and atheromatous aortas, whereas ACE-positive cells were localized in endothelial cells of normal aorta and in macrophages of atheromatous neointima. The density of chymase- and tryptase-positive mast cells in the atherosclerotic lesions was slightly but not significantly higher than that in the normal aortas, and the number of activated mast cells in the aneurysmal lesions (18%) was significantly higher than in atherosclerotic (5%) and normal (1%) aortas. Our results suggest that local Ang II formation is increased in atherosclerotic lesions and that chymase is primarily responsible for this increase. The histologic localization and potential roles of chymase in the development of atherosclerotic lesions appear to be different from those of ACE.
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PMID:Increased chymase-dependent angiotensin II formation in human atherosclerotic aorta. 1037 23

Human mast cells, by elaborating various cytokines, chemokines and proinflammatory mediators play a complex role in several allergic and inflammatory disorders. Mast cells have been identified in human heart tissue in close proximity to the sarcolemma, in perivascular and adventitial locations and in the shoulder region of coronary atheroma. Human heart mast cells (HHMC) can be isolated from patients undergoing heart transplantation and can be immunologically activated in vitro to induce the release of tryptase, chymase, cysteinyl leukotriene C4 and prostaglandin D2. Several cytokines (e.g., stem cell factor and TNF-alpha) reside in secretory granules of HHMC. Mast cell density is increased in the hearts of patients with ischemic and idiopathic dilated cardiomyopathy. Cardiac mast cells might contribute to the evolution of atherosclerosis, dilated cardiomyopathy, cardiac and systemic anaphylaxis through the release of cytokines and vasoactive and proinflammatory mediators.
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PMID:Immunological modulation of human cardiac mast cells. 1048 92

Oxidative modifications of low-density lipoproteins (LDL) may contribute to the pathogenesis of atherosclerosis. Although the oxidation products of the lipid components of LDL have been studied extensively, less is known about the oxidation products of the apoprotein, apolipoprotein B-100. To identify the specific oxidative modifications, we oxidized LDL in the presence of Cu(2+), treated with DNPH, precipitated and delipidated the protein, digested the protein with trypsin, and analyzed the peptides by high-performance liquid chromatography. We isolated nine peptides that exhibited measurable absorbance at 365 nm, which is characteristic of hydrazones derived from DNPH and is not observed in peptides derived from unoxidized LDL. Unexpectedly, we obtained the same peptides with absorbance at 365 nm in Cu(2+)-oxidized LDL not treated with DNPH. N-terminal sequence analyses and mass spectrometry indicated that the peptides isolated from the Cu(2+)-oxidized LDL all contained kynurenine residues in place of Trp residues found in the native apoprotein. The product profile we observed in Cu(2+)-oxidized LDL was remarkably different from the profiles observed in LDL oxidized by HOCl or myeloperoxidase in vitro, and the preferential oxidation of Trp to kynurenine in Cu(2+)-catalyzed oxidation of LDL contrasts with the products observed following oxidation of LDL with HOCl or myeloperoxidase. Our studies to date support the working hypothesis that the specific products of protein oxidation are sufficiently distinct to be developed as biomarkers of proposed mechanisms of oxidation of LDL and biological molecules in other toxicities and diseases.
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PMID:Identification of modified tryptophan residues in apolipoprotein B-100 derived from copper ion-oxidized low-density lipoprotein. 1062 56

Arterial wall lipid retention is believed to be due primarily to ionic interactions between lipoproteins and proteoglycans. Thus, oxidized low density lipoproteins (LDL), with decreased positive charge relative to native LDL, should have decreased interaction with negatively charged proteoglycans. However, oxidized LDL does accumulate within arterial lesions. Therefore, this study investigated the binding of native and oxidized LDL to a complex smooth muscle extracellular matrix and the role of ionic charge interactions in their binding. LDL was modified with 2,2-azo-bis(2-amidinopropane)-2HCl, hypochlorite, soybean lipoxygenase, and phospholipase or copper sulfate. The extracellular matrix had 15- to 45-fold greater binding capacity for the different forms of oxidized LDL than for native LDL. However, the affinity of binding for all forms of oxidized LDL was high (K(a) = approximately 10(-9) M) and was similar to that for native LDL. Preincubation of the lipoproteins with chondroitin sulfate decreased the binding of native LDL, but had no effect on the binding of oxidized LDL. Digestion of matrices with chondroitin ABC lyase and heparinase decreased the binding of native LDL, but increased the binding of oxidized LDL; matrix digestion with pronase or trypsin markedly reduced the binding of both native and oxidized LDL.Thus, the binding of native LDL involves matrix proteoglycans, whereas the binding of oxidized LDL involves a nonproteoglycan component(s) of the matrix. The markedly enhanced retention of oxidized LDL compared with native LDL may play an important role in the progression of atherosclerosis.
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PMID:Oxidized LDL bind to nonproteoglycan components of smooth muscle extracellular matrices. 1135 90

Mast cells are multifunctional, tissue-dwelling cells capable of secreting a wide variety of mediators. They develop from bone marrow-derived progenitor cells, primed with stem cell factor (SCF), which mediates its actions by interacting with the SCF receptor or c-kit on the cell surface. Mast cells continue their maturation and differentiation in peripheral tissue, developing into two well described subsets of cells, MCT and MCTC cells, varying in content of tryptase and chymase as well as in immunobiology. Mast cells are activated by numerous stimuli, including antigen (acting via the high affinity IgE receptor, Fc?RI), superoxides, complement proteins, neuropeptides and lipoproteins resulting in activation and degranulation. Following activation, these cells express mediators such as histamine, leukotrienes and prostanoids, as well as proteases, and many cytokines and chemokines, pivotal to the genesis of an inflammatory response. Recent data suggests that mast cells may play an active role in such diverse diseases as atherosclerosis, malignancy, asthma, pulmonary fibrosis and arthritis. Mast cells directly interact with bacteria and appear to play a vital role in host defense against pathogens. Drugs, such as glucocorticoids, cyclosporine and cromolyn have been demonstrated to have inhibitory effects on mast cell degranulation or mediator release.
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PMID:The human mast cell: functions in physiology and disease. 1153 8


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