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)

The major characteristics of human atherosclerotic lesions are similar to those of a chronic inflammatory reaction, namely fibrosis, mesenchymal cell proliferation, the presence of resident macrophages, and cell necrosis. Atherosclerosis exhibits in addition the feature of lipid (mainly cholesterol) accumulation. The results of the present report demonstrate that a specific cholesterol-containing lipid particle present in human atherosclerotic lesions activates the complement system to completion. Thus, lipid could represent a stimulatory factor for the inflammatory reaction, whose underlying mechanistic basis may be, at least in part, complement activation. The complement-activating lipid was purified from saline extracts of aortic atherosclerotic lesions by sucrose density gradient centrifugation followed by molecular sieve chromatography on Sepharose 2B. It contained little protein other than albumin, was 100-500 nm in size, exhibited an unesterified to total cholesterol ratio of 0.58 and an unesterified cholesterol to phospholipid ratio of 1.2. The lipid, termed lesion lipid complement (LCA), activated the alternative pathway of complement in a dose-dependent manner. Lesion-extracted low density lipoprotein (LDL) obtained during the purification procedure failed to activate complement. Specific generation of C3a desArg and C5b-9 by LCA indicated C3/C5 convertase formation with activation proceeding to completion. Biochemical and electron microscopic evaluations revealed that much of the C5b-9 present in atherosclerotic lesions is membraneous, rather than fluid phase SC5b-9. The observations reported herein establish a link between lipid insudation and inflammation in atherosclerotic lesions via the mechanism of complement activation.
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PMID:Isolation and characterization of a complement-activating lipid extracted from human atherosclerotic lesions. 237 93

Leaky endothelial junctions occurring during cell turnover have been postulated to be a major pathway for enhanced lipoprotein transport across the vascular endothelial layer, which leads to the development of atherosclerosis. Because hypertension has been well documented as one of the major risk factors for atherosclerosis, we explored the possibility that hypertension accelerates atherogenesis by increasing the turnover of endothelial cells and hence the transendothelial macromolecular permeability. The investigations were performed on thoracic aortas of 10 male 3-4-month-old spontaneously hypertensive rats and eight male age-matched Wistar-Kyoto normotensive rats. In en face preparations of aortic specimens, mitotic endothelial cells were identified by hematoxylin nuclear staining; dying or dead endothelial cells containing cytoplasmic immunoglobulin G were detected by indirect immunoperoxidase technique; and endothelial leakage to Evans blue-albumin conjugate was visualized by fluorescence microscopy. The number of leaky foci per unit endothelial surface area in spontaneously hypertensive rats was found to be approximately three times that in Wistar-Kyoto control rats; the frequencies of both endothelial cell mitosis and death in spontaneously hypertensive rats were also approximately three times the corresponding values in Wistar-Kyoto rats. These findings indicate that hypertension in spontaneously hypertensive rats is accompanied by increased endothelial cell turnover and an attendant enhancement of permeability to macromolecules.
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PMID:Transendothelial macromolecular transport in the aorta of spontaneously hypertensive rats. 237 48

Concentration and preferential retention of immunoglobulins and complement components were studied in comparison with other plasma proteins in 42 human aortae with atherosclerosis. Saline and acid extracted IgG, IgA, IgM, C1q, C3c, C4, C9, C3A, C-reactive protein, alpha 1-antitrypsin, alpha 2-macroglobulin, albumin, transferrin and fibrinogen were quantitatively determined using the radial immunodiffusion. The fibrous plaques and their adjacent areas contained higher levels of each protein than intima with only fatty streaks. No significant differences were found between the fibrous plaques and their adjacent areas presenting intimal thickenings. Saline eluted IgG and IgA were significantly higher in the fibrous plaque intima than in intimal samples with fatty streaks and were the only proteins detected in the acid eluates. The complement components were present in all saline eluates, while C-reactive protein was found in 23 samples. Crossed immunoelectrophoretic studies showed the activation of saline C3 and C4. In 8 cases serum levels of the studied proteins were compared with their concentration in saline eluates obtained from intima and media. The immunoglobulins and complement components presented higher intima/serum and lower media/intima retention ratios than the other studied proteins suggesting their preferential retention in the intima. The presence of immune related proteins in the atherosclerotic intima and their preferential retention might be explained not only by an altered permeability but also in relation to their function.
Atherosclerosis 1985 Apr
PMID:Immunoglobulins and complement components in human aortic atherosclerotic intima. 240 31

Protein extracted from 24 human aortic intimas (6-33 years old) with 9 M urea mixture, were studied after separation by two-dimensional gel electrophoresis (2-DE) and silver staining. The protein composition of normal intima in 4 cases, each without any gross changes in the thoracic aorta, displayed similarity. In each 2-DE protein pattern of these intimas about 150 polypeptide spots were detectable/mg of wet tissue. Major and medium polypeptides were described by relative molecular weight Mr in kilodaltons (kDa) and relative charge Cr. Major proteins found were actin (P44-18; Mr = 44 kDa; Cr = -18), tropomyosin-like proteins (P34-29, P35-28.5, P36-31) and two glycoproteins (G35-21, G35-23.5). Several new major and medium extracellular proteins were demonstrated in fibro-fatty lesions as well as in the lesion-free intimas adjacent to lesion in 3 cases. Many of these proteins appeared to originate from plasma: albumin, IgG, alpha 1-antitrypsin, transferrin, haptoglobin beta-chain, apo A-I, apo A-II, fibrinogen beta-chain, alpha 2-HS glycoprotein and alpha 1-antichymotrypsin. Visual comparison of intimal protein patterns from 17 different cases with varying degree of fatty streaks in the thoracic aorta, showed variability in 2 polypeptides P32-17.8 and P32-19.8 as well as 4 plasma proteins albumin, alpha 1-antitrypsin, transferrin and apo A-I. This study suggests that changes in protein composition may occur in the human aortic intima during the initial histological stages of atherogenesis providing potentially useful markers for their identification and pathophysiological evaluation.
Atherosclerosis 1986 May
PMID:Human aortic intima protein composition during initial stages of atherogenesis. 242 64

High circulating plasma levels of free fatty acids may injure endothelial cells, resulting in decreased barrier function of the vascular endothelium. The effect of media supplementation with varying concentrations of either linoleic (C18:2 omega 6) or linolenic acid (C18:3 omega 3) on albumin transfer across cultured endothelial monolayers was studied. A 24-h cell exposure to linoleic but not linolenic acid resulted in a concentration dependent and largely reversible increase in albumin transfer. Both fatty acids and in particular linolenic acid incorporated into cellular phospholipids. In contrast, only supplementation with linoleic but not linolenic acid resulted in an increased incorporation of this fatty acid into cell triglycerides. Similarly, only total cell triglyceride content increased after incubation with linoleic- but not with linolenic-enriched media. These results indicate that cellular enrichment with linoleic but not linolenic acid causes cellular perturbations that may be implicated in atherosclerosis.
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PMID:Linoleic acid and linolenic acid: effect on permeability properties of cultured endothelial cell monolayers. 256 26

The release of tissue plasminogen activator (tPA) by vascular endothelial cells during exercise was studied in forty men with insulin-dependent diabetes. Three groups, matched for age and diabetes duration, were defined as: group I (n = 19), normal urinary albumin excretion (less than 30 mg/24 h); group II (n = 11), incipient diabetic nephropathy (30-300 mg albumin excreted per 24 h); and group III (n = 10), clinical diabetic nephropathy (more than 300 mg albumin excreted per 24 h). Nine non-diabetic men served as controls. The rise in tPA antigen with exercise was similar in the controls and group I but significantly smaller in groups II and III (p less than 0.01). The albumin transcapillary escape rate was significantly higher in groups II and III than in group I and normal controls (p less than 0.01). The basal plasma level of von Willebrand factor was higher in groups III (p less than 0.01) and II (difference not significant, p = 0.06) than in group I and normal controls. These findings suggest that insulin-dependent diabetic patients with only slightly raised urinary albumin excretion have general endothelial cell dysfunction or damage. It is not yet clear whether these changes are important in the pathogenesis of thrombosis and atherosclerosis in these patients.
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PMID:Features of endothelial dysfunction in early diabetic nephropathy. 256 40

Elevated levels of plasma low density lipoprotein cholesterol (LDL) are associated with an increased incidence of atherosclerosis and its sequelae. A decrease in LDL levels correlates with a reduction in atherosclerosis. Drug therapy and diet have been moderately successful in lowering cholesterol levels, but require significant periods of treatment. Furthermore, a patient with genetically high LDL levels, as in familial hypercholesterolemia, may need a more rapid and reliable method of decreasing serum LDL. The present study was designed to test a device which can rapidly remove LDL from the circulation. The device consists of a filter cartridge filled with semipermeable hollow fibers which have a proprietary acidic polymer (pap) immobilized on the blood/plasma contacting surfaces; this polymer has been reported to selectively bind LDL cholesterol. The device was evaluated in a hypercholesterolemic rabbit model. Reductions in LDL serum concentration, ranging from 1.4-25.3%, occurred in 6/6 studies. All animals survived the procedure. Autopsy results at 10 days showed normal histology. Binding of other proteins (HDL, albumin) were minimal and no hemolysis was observed. Results of this preliminary study demonstrate the feasibility of reducing serum LDL levels with a hollow fiber device.
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PMID:A rabbit model for evaluation of an extracorporeal LDL removal system. 259 80

Age is strongly correlated to the onset of atherosclerotic lesion formation in humans. This may be associated with an age-related increase in the susceptibility of the vascular endothelium to oxidative injury. Such injury may result in altered endothelial function as a barrier to plasma components, such as cholesterol-rich lipoprotein remnants. To investigate this hypothesis, the relationship between endothelial cell culture age, susceptibility to oxidative injury and protection against this injury by the nutrient/antioxidant vitamin E on endothelial barrier function (transfer of albumin across endothelial monolayers) was examined. An acute 24 h exposure to 30 microM linoleic acid hydroperoxide resulted in increased albumin transfer at all cell passages tested (up to passage 50). Pre-enrichment of cells with 25 microM vitamin E always protected endothelial cells against oxidized fatty acid-induced cell injury, independent of cell age. In comparison, patterns of total cell protein and DNA were not markedly influenced by experimental treatments, although age-related declines in total DNA were noted. These data suggest that the possible correlation between age and the onset of atherosclerosis may be in part related to a decrease in endothelial barrier function due to oxidative stress, permitting more blood components to enter the arterial wall. Furthermore, vitamin E may protect endothelial cells against oxidant-mediated vascular injury.
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PMID:Protective effects of vitamin E in age-related endothelial cell injury. 259 93

The sensitive and reliable dinitrophenyl (DNP) hapten sandwich staining (DHSS) procedure (B. Jasani et al., Virchows Arch (Pathol. Anat.), 406 (1985) 441-448) was used to study the distribution of immunoperoxidase staining seen with antibodies to seven protein markers in post-mortem heart tissue. This was obtained from 12 cases with macroscopic myocardial infarction and 17 cases without myocardial infarction (10 with and 7 without significant coronary artery atherosclerosis). The immunostaining patterns were compared with the appearances seen in adjacent sections stained by the routine haematoxylin and eosin (H & E) and phosphotungstic acid haematoxylin (PTAH) methods and a method previously recommended for the detection of early myocardial infarction, the haematoxylin basic fuchsin picric acid (HBFP) stain. Loss of immunostaining with an antibody to myoglobin was found to be a reliable and more objective marker of both early and established myocardial infarction compared with the histological stains. Antibodies to myosin, caeruloplasmin, C-reactive protein and pre-albumin gave similar but less reliable results, whilst those to complement factor C3b and alpha-1 anti-trypsin gave the least reliable results for early myocardial ischaemic/hypoxic damage. The immunocytochemical results are considered sufficiently encouraging to extend the work to a large number of sudden death cases in order to establish a new, more reliable approach to the detection of histologically latent ischaemic/hypoxic damage in the myocardium.
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PMID:Immunocytochemical diagnosis of early myocardial ischaemic/hypoxic damage. 264 26

The rat aortic model of endothelial injury (balloon catheter induced) has been used to establish whether changes in protein intramural penetration in specific areas of the injured aorta were accompanied by phenotypic modifications of the regenerated endothelial cells covering these particular regions. Iodinated lipoproteins (IDL/LDL fraction) and albumin were used as tracers to localize protein permeability and retention in the aorta. Lipoproteins, but not albumin, were retained in the thickened areas covered with regenerated endothelium (i.e., 60 days after balloon induced injury). Neither lipoproteins nor albumin were retained in the other aortic areas studied, including the intimal thickening of de-endothelialized areas (15 days after injury). The relative volume of cytoplasmic stress fibers was significantly increased in regenerated endothelium covering thickened areas as compared with the other regions of the injured or normal aorta. The accumulation of lipids usually observed in atherosclerotic lesions, compatible with the trapping of lipoproteins by the matrix component of the intimal thickening, may be related to modulated features of endothelial cells regenerated over thickened areas of the aorta.
Atherosclerosis 1989 Apr
PMID:Actin stress fiber content of regenerated endothelial cells correlates with intramural retention of intermediate plus low density lipoproteins in rat aorta after balloon injury. 273 Jul 15


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