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)

Autogenous veins and polyester prostheses were implanted in the abdominal aorta of dogs. The venous or polyester grafts were removed together with sections of the normal arteries and veins 1 month, 4 months, and 3 years after the operation. This material was then dissected into the intimal, medial, and adventitial layers, and homogenized after which their cathepsin D activity was determined. It was found that the cathepsin D activity was far higher in all the layers of the venous grafts, particularly in the polyester grafts, than in the corresponding layers of the normal arteries and veins.
Atherosclerosis 1979 Jan
PMID:Cathepsin D activity of venous and polyester vascular grafts implanted in the abdominal aorta of the dog. 46 12

In order to obtain information about the changes in lysosomal enzyme activities in arterial endothelial cells under hypertensive conditions, a biochemical study was performed on 5 lysosomal enzymes, acid phosphatase, N-acetyl-beta-glucosaminidase (NAGase), cathepsin B, cathepsin D and beta-glucuronidase, in endothelial cells isolated by an enzymatic technique from the aorta of spontaneously and renal hypertensive rats, and normotensive control rats. The aortic endothelial cells in the old spontaneously and the renal hypertensive rats showed increased activities of enzymes examined in comparison with those in the age-matched control rats. Endothelial cells in young spontaneously hypertensive rats did not show any elevated enzyme activities compared with those in the controls, and the enzyme activities tended to increase with aging. From this, it is deduced that hypertension activates lysosomal enzyme activities in aortic endothelial cells. The differences in the activities of NAGase, cathepsin B and cathepsin D between hypertensive and control animals increased markedly with advancing age. These activated lysosomal enzymes seem to be involved in the developmental mechanism of arterial endothelial cell injury in hypertension and in further development of hypertensive vascular changes.
Atherosclerosis 1988 Mar
PMID:Effect of hypertension on lysosomal enzyme activities in aortic endothelial cells. 335 16

The development of a model of chronic myocardial ischemic injury (MII) in rabbits by administering increasing doses of isoproterenol (ISO) is described. Repeated s.c. injections of increasing doses of ISO (0.5 mg/kg, on day 1 to 15.5 mg/kg, on day 15) resulted in an increase in serum glucose, free fatty acids and creatine phosphokinase. Examination of hearts from ISO-treated rabbits revealed marked hypertrophy of the left ventricle and an increase in total water content. Biochemical analysis showed an increase in left ventricular hydroxyproline and a decrease in ATP and glycogen content following ISO-treatment. Ion measurements revealed extensive accumulation of Na and Ca, with the Ca being preferentially accumulated in the mitochondria. Measurement of subcellular organelle marker enzymes showed decreases in the sarcolemmal Na+-K+-stimulated (ouabain-sensitive), mitochondrial (azide-sensitive) and sarcoplasmic reticulum ATPase activities in the ISO-treated animals. Analysis of lysosomal enzyme activities in myocardial homogenates showed significant decreases in the latency of N-acetyl-beta-glucosaminidase and cathepsin D. The above biochemical alterations in ISO-induced MII generally parallel changes previously seen in the rabbit following acute coronary artery ligation. The present model allows the study of MII uncomplicated by some uncertainties arising from the surgical or anesthetic procedures employed in acute "open-chest" preparations and would permit long-term follow-up studies of pharmacological interventions. The susceptibility of the rabbit to experimental atherosclerosis should allow the development of an experimental model of MII which more closely approximates the clinical situation.
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PMID:Myocardial ischemic injury induced by isoproterenol in the rabbit: biochemical and chemical alterations. 385 Jul 74

Low density lipoproteins have been implicated in the pathogenesis of atherosclerosis. A study has therefore been made of their proteolytic degradation by homogenates of cultured smooth muscle cells from the pig aorta. The pH optimum of proteolysis of 125I-labelled low density lipoproteins was 4.25, thus suggesting the involvement of lysosomal cathepsins. Proteolysis at acid pH started to become saturated at low density lipoprotein concentrations of approx. 20 microgram of protein/ml, but did not obey Michaelis-Menten kinetics. After a lag period of approx. 10 min, proteolytic degradation was linear with time up to at least 4 h incubation, but showed a sigmoidal relationship with homogenate concentration. When cathepsin D was inhibited by pepstatin, the proteolysis of 125I-labeled low density lipoproteins was inhibited by more than 90%, whereas when cathepsin B was inhibited by leupeptin, the rate of proteolysis decreased by approx. 50%. Antipain, which inhibits both cathepsins A and B, did not inhibit proteolysis any more than leupeptin, thus suggesting a minor role, if any, for cathepsin A. a combination of pepstatin and either leupeptin or antipain inhibited proteolysis completely. Cathepsins B and D acted synergistically in the degradation of 125I-labelled low density lipoproteins.
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PMID:Proteolytic degradation of low density lipoproteins by arterial smooth muscle cells: the role of individual cathepsins. 701 93

The monocyte/macrophage plays a central role in fibrinolysis. Cell-surface of components of the plasminogen activator system leads to the elaboration of plasmin, which facilitates degradation of fibrin in the pericellular environment, as well as activation of matrixins, which promote degradation of matrix components. Fibrin degradation also occurs by way of a proteolytic system within the macrophage lysosome that does not involve plasmin. This alternate pathway involves first the binding of fibrin(ogen) to the surface integrin Mac-1 (CD11b/CD18) followed by internalization of the complex into the lysosome where the aspartyl protease cathepsin D degrades the protein. These molecular events underlie the many physiologic and pathophysiologic processes in which the monocyte/macrophage is involved, including adhesion, migration, matrix degradation and remodeling, wound healing, fibrinolysis, and atherosclerosis.
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PMID:The macrophage and fibrinolysis. 912 15

The subfraction of low density lipoprotein (LDL) with low sialic acid content that caused accumulation of cholesterol esters in human aortic smooth muscle cells has been found in the blood of coronary atherosclerosis patients. It was demonstrated that this subfraction consists of LDL with small size, high electronegative charge, reduced lipid content, altered tertiary structure of apolipoprotein B, etc. LDL of this subfraction is naturally occurring multiple-modified LDL (nomLDL). In this study we compared the binding, uptake and proteolytic degradation of native LDL and nomLDL by smooth muscle cells cultured from human grossly normal intima, fatty streaks, and atherosclerotic plaques. Uptake of nomLDL by normal and atherosclerotic cells was 3.5- and 6-fold, respectively, higher than uptake of native LDL. Increased uptake of nomLDL was due to increased binding of this LDL by intimal smooth muscle cells. The enhanced binding is explained by the interaction of nomLDL with cellular receptors other than LDL-receptor. Modified LDL interacted with the scavenger receptor, asialoglycoprotein receptor, and also with cell surface proteoglycans. Rates of degradation of nomLDL were 1.5- and 5-fold lower than degradation of native LDL by normal and atherosclerotic cells, respectively. A low rate of nomLDL degradation was also demonstrated in homogenates of intimal cells. Activities of lysosomal proteinases of atherosclerotic cells were decreased compared with normal cells. Pepstatin A, a cathepsin D inhibitor, completely inhibited lipoprotein degradation, while serine, thiol, or metallo-proteinase inhibitors had partial effect. This fact reveals that cathepsin D is involved in initial stages of apoB degradation by intimal smooth muscle cells. Obtained data show that increased uptake and decreased lysosomal degradation of nomLDL may be the main cause of LDL accumulation in human aortic smooth muscle cells, leading to foam cell formation.
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PMID:Metabolism of native and naturally occurring multiple modified low density lipoprotein in smooth muscle cells of human aortic intima. 943 79

The cytotoxicity of oxidized LDL (oxLDL) to several types of artery wall cells might contribute to atherosclerosis by causing cell death, presumably by both apoptosis and necrosis. After its uptake into macrophage lysosomes by receptor-mediated endocytosis, oxLDL is poorly degraded, resulting in ceroid-containing foam cells. We studied the influence ofoxLDL on lysosomal enzyme activity and, in particular, on lysosomal membrane stability and the modulation of these cellular characteristics by HDL and vitamin E (vit-E). Unexposed cells and cells exposed to acetylated LDL (AcLDL) were used as controls. The lysosomal marker enzymes cathepsin L and N-acetyl-beta-glucosaminidase (NAbetaGase) were biochemically assayed in J-774 cells after fractionation. Lysosomal integrity in living cells was assayed by the acridine orange (AO) relocation test. Cathepsin D was immunocytochemically demonstrated in J-774 cells and human monocyte-derived macrophages. We found that the total activities of NAbetaGase and cathepsin L were significantly decreased, whereas their relative cytosolic activities were enhanced, after oxLDL exposure. Labilization of the lysosomal membranes was further proven by decreased lysosomal AO uptake and relocation to the cytosol of cathepsin D, as estimated by light and electron microscopic immunocytochemistry. HDL and vit-E diminished the cytotoxicity of oxLDL by decreasing the lysosomal damage. The results indicate that endocytosed oxLDL not only partially inactivates lysosomal enzymes but also destabilizes the acidic vacuolar compartment, causing relocation of lysosomal enzymes to the cytosol. Exposure to AcLDL resulted in its uptake with enlargement of the lysosomal apparatus, but the stability of the lysosomal membranes was not changed.
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PMID:Uptake of oxidized LDL by macrophages results in partial lysosomal enzyme inactivation and relocation. 948 81

Production of alpha-1-antitrypsin by human monocytes is an important factor in controlling tissue damage by proteases in the microenvironment of inflammation. Increases of four- to eightfold in levels of native and fragmented forms of alpha-1-antitrypsin have been detected in inflammatory loci in vivo. In this study we have extended our previous observation that the carboxyl-terminal peptide (C-36) of alpha-1-antitrypsin produced by specific proteinase cleavage, when added in its fibrillar form at concentrations of 5 microM or more to monocytes in culture, induces cytotoxic effects. Experiments with synthetic amyloid-forming peptides suggest fibril cytotoxicity to be mediated via a common oxidative stress mechanism. We undertook to determine whether C-36 fibril cytotoxicity also involves this common pathway. Monocytes stimulated with C-36 fibrils for 1 h showed significant elevation in monocyte chemoattractant protein-1 expression, induced reduced nicotinamide-adenine dinucleotide phosphate oxidase activity, increased intracellular lipid peroxidation, altered mitochondrial membrane potential, and increased cytosolic cytochrome c and caspase-3 activity. Treatment of monocytes with C-36 fibrils after 24 h also resulted in increased cytosolic cathepsin D activity, suggesting that lysosomes may also be destabilized over longer periods of time. In contrast, native alpha-1-antitrypsin only showed concentration and time-dependent effects on chemoattractant protein-1 expression, and these appear to be independent of oxidative stress. These results indicate that the cytotoxicity of the fibrillar fragment is mediated via oxidative mechanisms and support important multiple roles for native and also for cleaved forms of alpha-1-antitrypsin in monocyte recruitment and activation during inflammatory processes such as atherosclerosis.
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PMID:Fibrillogenic C-terminal fragment of alpha-1-antitrypsin activates human monocytes via oxidative mechanisms. 1151 75

Atherosclerosis, and the resulting coronary heart disease and stroke, is the most common cause of death in developed countries. Atherosclerosis is an inflammatory process that results in the development of complex lesions or plaques that protrude into the arterial lumen. Plaque rupture and thrombosis result in the acute clinical complications of myocardial infarction (MI) and stroke. Although certain risk factors (dyslipidemias, diabetes, hypertension) and humoral markers of plaque vulnerability (C-reactive protein, interleukin-6, 10 and 18, CD40L) have been identified, a highly sensitive and specific biomarker or protein profile, which could provide information on the stability/vulnerability of atherosclerotic lesions, remains to be identified. In this review, we report several proteomic approaches which have been applied to circulating or resident cells, atherosclerotic plaques or plasma, in the search for new proteins that could be used as cardiovascular biomarkers. First, an example using a differential proteomic approach (2-DE and MS) comparing the secretome from control mammary arteries and atherosclerotic plaques is displayed. Among the different proteins identified, we showed that low levels of HSP-27 could be a potential marker of atherosclerosis. Second, we have revised several studies performed in cells involved in the pathogenesis of atherosclerosis (foam cells and smooth muscle cells). Another approach consists of performing proteomic analysis on circulating cells or plasma, which will provide a global view of the whole body response to atherosclerotic aggression. Circulating cells can bear information reflecting directly an inflammatory or pro-coagulant state related to the pathology. As an illustration, we report that circulating monocytes and plasma in patients with acute coronary syndromes has disclosed that mature Cathepsin D is increased both in the plasma and monocytes of these patients. Finally, the problems of applying proteomic approach directly to plasma will be discussed. The purpose of this review is to provide the reader with an overview of different proteomic approaches that can be used to identify new biomarkers in vascular diseases.
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PMID:Quest for novel cardiovascular biomarkers by proteomic analysis. 1608 68

The mechanisms by which hydroxymethylglutaryl CoenzymeA reductase inhibitors (statins) reduce atherosclerotic cardiovascular morbidity and mortality remain poorly understood. Statins have been shown to modulate the levels of different inflammatory proteins both in carotid atherosclerotic plaques and in the blood of patients with atherosclerosis. In this work, we hypothesize that statins could also modulate the levels of the proteins secreted by cultured atherosclerotic plaques. Thus, the secretomes obtained from complicated atherosclerotic plaques incubated in the presence/absence of atorvastatin (10 micromol/l, 24 h) were analysed and compared by two-dimensional electrophoresis, considering the fibrous adjacent areas as controls. In total, 54 proteins (83 protein isoforms) were identified by Mass Spectrometry (MS): 24 proteins were increased and 20 proteins decreased in atheroma plaque supernatants compared to controls. Some of these proteins, like Cathepsin D, could play a significant role in plaque instability, becoming a potential target for therapeutical treatment. Interestingly, 66% of the proteins differentially released by atherosclerotic plaques reverted to control values after administration of atorvastatin, among them, Cathepsin D. Moreover, plaques obtained from patients who received atorvastatin treatment prior to carotid endarterectomy showed decreased Cathepsin D expression relative to plaques from non-treated patients. In conclusion, this proteomic approach has shown that statins are able to modulate the secretome of atherosclerotic plaques, and new therapeutical targets for statins have been characterised.
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PMID:Atorvastatin modulates the profile of proteins released by human atherosclerotic plaques. 1733 87


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