Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The initiation of atherosclerosis may result from blood flow oscillatory shear stress in certain vascular sites (bending points, bifurcations, etc.) producing chronic minimal injury resulting in functional alteration of the arterial endothelium type I injury; experimentally, this is potentiated by atherogenic risk factors such as hypercholesterolemia, hypertension, immunocomplexes, viral infections, and tobacco smoke. Such minimal injury leads to accumulation of lipid and monocytes (macrophages), and subsequently, toxic products released by the macrophages produce damage of the intimal surface with denuding endothelium type II injury or damage, which attracts platelets; all of these cells release growth factors, prompting migration and proliferation of smooth muscle cells and producing a "fibro-intimal lesion" or the outside of the capsule of a predominant "lipid lesion." The lipid lesions surrounded by a thin capsule tend to be small and rupture easily, causing type III injury or damage; that is, they are soft and weak, contain large numbers of macrophages, which may release collagenase and elastase to form abscesses, and by their location, are under the effect of flow shear forces. After plaque disruption there is thrombus formation; when thrombi are small, they can become organized and contribute to the growth of the atherosclerotic plaque; when thrombi are large and occlusive, they lead to the acute coronary syndromes. New data suggest that, at the time of plaque disruption, certain "thrombogenic" risk factors modulate the degree of thrombogenicity and, thereby, the growth of the plaque versus the various acute coronary syndromes. Aside from the need for better understanding of the basic biology of atherogenesis, emphasis on identifying and modifying the primary atherogenic and thrombogenic risk factors should continue for primary prevention. Also, new approaches should focus on the identification, stabilization, and regression of the small "lipid plaques" prone to rupture (these are not necessarily angiographically apparent), as well as on the use of better and safer antithrombotic agents for prevention of progression.
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PMID:Clinical-pathological correlations of coronary disease progression and regression. 142 42

These experiments were designed to determine whether hypercholesterolemia and the accumulation of cholesterol or cholesteryl esters in rabbit carrageenan granuloma macrophages might influence selected markers of macrophage activation. Granulomas induced by subcutaneous injection of carrageenan into rabbits were harvested after 4, 14, and 28 days. Macrophages were isolated from granuloma tissues by collagenase digestion and cultured overnight. Secretion of lysosomal beta-glucuronidase, membrane 5'-nucleotidase, cellular plasminogen activator, and superoxide anion generation were measured as markers of activation. beta-Glucuronidase activity secreted into the media by granuloma macrophages from normocholesterolemic (NC) and hypercholesterolemic (HC) rabbits showed a trend toward an increase with time between 4 and 14 days in both groups. This was confirmed in a separate experiment with a significant increase by 14 days, together with a significantly greater secretion by NC macrophages and a significantly elevated level of cellular beta-glucuronidase activity in NC relative to HC macrophages. Activity of the membrane ectoenzyme 5'-nucleotidase was minimal in lysates of NC or HC macrophages, in contrast to freshly isolated human monocytes, indicating that both NC and HC granuloma macrophages were highly activated. Cellular plasminogen activator activity was significantly increased between 4 and 14 days, and was significantly greater in HC than in NC macrophages at 14 days. Stimulation of macrophages with phorbol myristate acetate increased superoxide anion generation by both NC and HC macrophages; however, no difference in superoxide anion generation was observed between macrophages from NC and HC rabbits. On the basis of the 5'-nucleotidase findings, it is concluded that both the NC and HC granuloma macrophages are highly activated, and further that hypercholesterolemia does not enhance macrophage generation of superoxide anion, either spontaneously or as the result of phorbol myristate acetate stimulation. Although hypercholesterolemia results in macrophage activation in terms of an increased cellular plasminogen activator activity, the secretion of the lysosomal enzyme beta-glucuronidase is diminished. Thus, hypercholesterolemia associated with macrophage cholesterol and cholesteryl ester accumulation has no consistent overall influence on activation, a finding of potential importance in the context of atherogenesis.
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PMID:Influence of hypercholesterolemia and cholesterol accumulation on rabbit carrageenan granuloma macrophage activation. 283 4

Characteristics of lipoprotein receptors of the isolated liver parenchymal cells prepared from the streptozotocin-induced diabetic rats were investigated. Streptozotocin-induced diabetic rats fed 1.0% cholesterol showed the exaggerated hypercholesterolemia as compared to control rats fed 1.0% cholesterol. The present study was designed to elucidate the role of lipoprotein receptor mechanisms of liver parenchymal cells in the diabetic dyslipoproteinemia. 125I-labeled lipoproteins (rat beta-VLDL, human LDL2 or rat HDL3) were incubated with liver parenchymal cells isolated by liver perfusion using collagenase. According to the Scatchard analysis, the apparent dissociation constant (kd) and maximum beta-VLDL binding (Bmax) for the higher affinity binding site in the diabetic rats (n = 6) were (11.9 +/- 5.1) X 10(2) ng/ml and 307.5 +/- 145.2 ng/10(6) cells, respectively. These binding characteristics of the diabetic rats were not significantly different from the control rats. Furthermore, there were no significant differences in the binding characteristics of human LDL2 and rat HDL3 between the diabetic rats and the control rats. The data presented suggest that significant role of alteration of lipoprotein receptor characteristics in liver parenchymal cells is not played in the diabetic dyslipoproteinemia.
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PMID:Characteristics of lipoprotein receptors of the isolated liver parenchymal cells prepared from the streptozotocin-induced diabetic rats. 300 89

With an increasing interest in the role of the monocyte-macrophage in the pathogenesis of atherosclerosis and as a progenitor of plaque intimal foam cells, a model for the study of foam-cell differentiation in an extravascular environment has been developed. Granulomas were induced in 25 normocholesterolemic (NC) and 28 hypercholesterolemic (HC) rabbits by the subcutaneous injection of 15 ml of 1% carrageenan. Granuloma tissue was harvested at 4, 7, 14, and 28 days and studied by light and transmission electron microscopy. Macrophages and foam cells were isolated by enzymic dispersion with collagenase and cultured for further characterization by scanning electron microscopy, nonspecific esterase (NSE), and oil red O (ORO) staining. Granuloma macrophages from NC rabbits were consistently ORO-negative, contrasting with those from HC rabbits which were strongly ORO-positive, even at 4 and 7 days. With an increasing duration of exposure to hypercholesterolemia, macrophages accumulated increasing amounts of stainable lipid, and in the 28-day HC granulomas, large foam cells distended by lipid inclusions accounted for 70% of the cells present. This model has established that NSE-positive macrophages in HC granulomas accumulate lipid and assume the morphologic characteristics of atheromatous intimal foam cells.
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PMID:Evolution of foam cells in subcutaneous rabbit carrageenan granulomas: I. Light-microscopic and ultrastructural study. 396 33

Rabbits were fed with normal (group 1 and 2) and cholesterol rich diets (group 3 and 4) concomitantly to a daily peroral administration of 50 mg/kg procyanidolic oligomers (PCO) to groups 2 and 4. After 10 weeks, the cholesterol content of the blood serum and the excised aortic intima-media were significantly higher in groups 3 and 4 than in groups 1 and 2. The DNA, hydroxyproline, uronic acid contents were similar in aortic dry weight basis in all four groups. The intima-media samples were extracted successively with 0.15 M NaCl, 0.02 M sodium phosphate pH 7.4 (NaCl extract) and with 4 M guanidinium chloride, 0.05 M sodium acetate pH 5.8 prior (G1 extract) and following (G2 extract) hydrolysis of the collagen with collagenase. The cholesterol contents of G1 extracts were higher in groups 2 and 4 than in groups 1 and 3. The cholesterol content of aortic elastin increased with cholesterol feeding (group 3). With simultaneous administration of cholesterol and PCO the cholesterol content of aortic elastin in group 4 was significantly lower than in group 3. The uronic acid contents increased in G1 extracts and in the collagenase digest with PCO treatment of both normal and hypercholesterolemic rabbits. The ratio of dermatan-sulphate to chondroitin-sulphate decreased with hypercholesterolemia (group 3) and with PCO (group 2 and 4). The parallelism between increased cholesterol and uronic acid contents and modified glycosaminoglycan composition in G1 extract, indicate that the interaction of cholesterol with macromolecules of the aorta can be modulated by PCO. This drug modifies the extractibility of aortic cholesterol and glycosaminoglycans and reduces the association of cholesterol to elastin.
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PMID:The effect of procyanidolic oligomers on the composition of normal and hypercholesterolemic rabbit aortas. 649 5

Dynamics of lipoprotein-glycosaminoglycan interactions in aortas were studied in vivo using the atherosclerotic rabbit model. Severe hypercholesterolemia and atherosclerosis were produced by relatively long-term feeding of a high cholesterol diet. [35S]Sulfate uptake by aorta was measured to assess the sulfated glycosaminoglycan metabolism while the plasma and aorta distribution of 125I-labeled LDL after intravascular injection was determined to monitor aortic LDL uptake and complex formation with glycosaminoglycans. The retention and distribution of LDL as lipoprotein-glycosaminoglycan complexes in different extracellular connective tissue elements were evaluated by extracting the tissues with saline, collagenase and elastase. Hypercholesterolemia with atherosclerosis resulted in a several-fold increase in the uptake of LDL by aorta despite a marked reduction of 125I-labeled LDL in the plasma compartment and in a significant increase in glycosaminoglycan content of aorta coupled with an increased 35S incorporation into glycosaminoglycans. Elastase-solubilized fractions from normal aortas and collagenase-solubilized fractions from atherosclerotic aortas contained maximum labeled and nonlabeled glycosaminoglycan, suggesting alterations in the make-up of fibrous structures of connective tissue matrix in atherosclerosis. Saline extraction and collagenase and elastase digestions solubilized varied proportions of lipoprotein-cholesterol and 125I-labeled LDL, thereby representing different pools of extracellular matrixbound lipoproteins. A tendency for 125I-labeled LDL to increase in collagenase- and elastase-solubilized fractions with time (4 h vs. 24 h) was noted. The occurrence of both lipoproteins and glycosaminoglycan (labeled and nonlabeled) in the ultracentrifugal floating fraction at solvent density 1.063 g/ml demonstrated that the lipoproteins solubilized by different extraction procedures occur in part as lipoprotein-glycosaminoglycan complexes. The specific activities of glycosaminoglycan in the complexes obtained by different extraction procedures differed markedly (elastase greater than collagenase greater than saline), emphasizing the presence of different pools of complexes. Thus, besides arterial cell-mediated processes, extracellular matrix components are important in affecting the retention and accumulation of LDL in atherosclerosis.
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PMID:Dynamics of lipoprotein-glycosaminoglycan interactions in the atherosclerotic rabbit aorta in vivo. 671 64

Monocyte-derived foam cells figure prominently in rupture-prone regions of atherosclerotic plaques. Peripheral blood monocytes in culture can produce certain enzymes that degrade extracellular matrix, known as matrix metalloproteinases (MMPs). Lipid-laden macrophages may thus contribute to weakening of extracellular matrix of rupture-prone atherosclerotic plaques. However, the spectrum and regulation of MMP production by foam cells remain unknown. To investigate this issue, we isolated lipid-laden macrophages from rabbit aortic lesions produced by a combination of hypercholesterolemia and balloon injury. Freshly isolated aortic macrophage foam cells, identified using cell-specific antibodies, contained immunoreactive stromelysin and interstitial collagenase, whereas alveolar macrophages isolated from the lungs of same rabbits did not. Macrophages from both tissue sources released gelatinolytic activity consistent with the 92-kDa gelatinase. In vitro, lipid-laden aortic macrophages, but not alveolar macrophages, synthesized de novo and released immunoprecipitable stromelysin and collagenase, with or without stimulation by phorbol ester or bacterial lipopolysaccharide. These stimuli caused foam cells to release additional gelatinolytic activity that migrated faster than a purified preparation of 92-kDa gelatinase in substrate-containing polyacrylamide gels, indicating activation of the 92-kDa gelatinase or induction of the 72-kDa gelatinase. Our results show that lipid-laden macrophages elaborate MMPs capable of degrading the major constituents of vascular extracellular matrix even without further stimulation. Therefore, these cells may contribute to remodeling of the extracellular matrix during atherogenesis and to the disruption of plaques often responsible for acute clinical manifestations of atherosclerosis.
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PMID:Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. 783 Dec 99

Hyperlipidemia, especially hypercholesterolemia, may contribute to glomerulosclerosis as it does to atherosclerosis. Low density lipoprotein (LDL) stimulates the production of extracellular matrix by mesangial cells in culture as well as the proliferation of mesangial cells. This study was carried out to examine the effects of LDL on the type IV collagen (CIV) production by cultured rat mesangial cells (CRMC). Subconfluent CRMC monolayers which were grown in RPMI with 20% lipid-free fetal calf serum for 48 h were challenged with LDL (0, 50, 100, 150 and 200 micrograms/ml) for another 48 h. LDL was prepared from normal human plasma. Mesangial cell proliferation was examined by [3H]-thymidine uptake. Production of CIV was evaluated as the expression of CIV on the cell surface by flow-cytometric analysis. The collagen synthesis was measured by the [3H]-proline uptake. Total RNA was extracted from CRMC at 6 and 24 h of incubation with 150 micrograms/ml LDL, and Northern blotting and hybridization was performed with cDNAs for alpha 1-CIV, for 72-kD collagenase and for tissue inhibitor of metalloproteinase (TIMP)-2. The amount of total mRNA was corrected with beta-actin mRNA. Mesangial cell proliferation increased in all concentrations studied and had a peak value of 221% with 150 micrograms/ml of LDL. Expression of CIV increased by 30-60% in 100-200 micrograms/ml of LDL. Collagen synthesis also increased by 50-70% in 150-200 micrograms/ml of LDL. The mRNA ratio (procollagen alpha 1(IV)/beta-actin) increased to 133% at 24 h. The mRNA ratio (TIMP-2/beta-actin) increased to 137% at 24 h. mRNA ratios at 6 h showed no change.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of low density lipoprotein on type IV collagen production by cultured rat mesangial cells. 793 24

Some components of plasma and granulocyte proteolytic system, granulocyte activation degree were evaluated in 15 patients with nonspecific aortic arteritis (NAA) and 12 hereditary hypercholesterolemia (HHC) patients. Catepsin G activity in blood plasma of NAA and HHC patients was higher than in donors 8-9 and 6-fold, respectively (p < 0.001). Granulocyte collagenase activity, spontaneous NBT test values in them were higher than in donors 6 and 4-fold (p < 0.02 and p < 0.01, respectively), 2-fold (p < 0.005 and p < 0.001, respectively). The data obtained confirm the suggestion on the presence of an inflammatory component not only in pathogenesis of NAA, but also in HHC causation.
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PMID:[The biochemical and clinical aspects of the participation of granulocytes and their proteinases in a vascular wall lesion]. 908 9

Degradation of extracellular matrix, particularly interstitial collagen, promotes plaque instability and contributes to restenosis after vascular injury. We have explored the effects of vitamins C and E on the collagen content and metalloproteinase-1 (MMP-1) expression after angioplasty in hypercholesterolemic pigs. Iliac angioplasty was performed on 18 minipigs divided into three diet groups: a normal-cholesterol (NC), a high-cholesterol (HC) and a high-cholesterol plus vitamins C+E (HCV). Four weeks later, after sacrifice, the vascular collagen content and MMP-1 protein expression, along with the plasma caseinolytic activity and lipid peroxidation, were measured. MMP-1 was also determined in arterial rings stimulated with native low-density lipoproteins (LDL) isolated from experimental groups. Cholesterol-rich diet augmented plasma lipid peroxidation (P<0.05), reduced the collagen content and increased vascular MMP-1 expression after injury (P<0.05). Enhanced caseinolytic activity (identified as MMP-1) was also observed in HC plasma samples and in supernatants from arterial rings incubated with HC-LDL. Vitamins C and E markedly increased neointimal collagen content (P<0.01), reduced the hypercholesterolemia-induced changes in vascular MMP-1 (P<0.05) and diminished plasma and ex vivo caseinolytic activity. Vitamins C and E may help stabilize atherosclerotic plaque after angioplasty and favor vascular remodeling by increasing collagen content and reducing vascular MMP-1 expression in porcine hypercholesterolemia.
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PMID:Antioxidant vitamins increase the collagen content and reduce MMP-1 in a porcine model of atherosclerosis: implications for plaque stabilization. 1261 67


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