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)

Elastin, the main component of the extracellular matrix of arteries, was thought to have a purely structural role. Disruption of elastin was believed to lead to dissection of arteries, but we showed that mutations in one allele encoding elastin cause a human disease in which arteries are blocked, namely, supravalvular aortic stenosis. Here we define the role of elastin in arterial development and disease by generating mice that lack elastin. These mice die of an obstructive arterial disease, which results from subendothelial cell proliferation and reorganization of smooth muscle. These cellular changes are similar to those seen in atherosclerosis. However, lack of elastin is not associated with endothelial damage, thrombosis or inflammation, which occur in models of atherosclerosis. Haemodynamic stress is not associated with arterial obstruction in these mice either, as the disease still occurred in arteries that were isolated in organ culture and therefore not subject to haemodynamic stress. Disruption of elastin is enough to induce subendothelial proliferation of smooth muscle and may contribute to obstructive arterial disease. Thus, elastin has an unanticipated regulatory function during arterial development, controlling proliferation of smooth muscle and stabilizing arterial structure.
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PMID:Elastin is an essential determinant of arterial morphogenesis. 960 66

The structure of medial elastin determines arterial function and affects wall mechanical properties. The aim of this study was to (1) characterize the structure of elastin in terms of textural features, (2) relate structural parameters to total number of cardiac cycles (TC), and (3) determine the contribution of medial elastin to lumen mechanical stress. Images of pressure-fixed aortic sections stained for elastin were obtained from specimens collected postmortem from 35 animals of different species with a wide range of age, heart rate, and TC and divided into 2 groups: TClow=3.69+/-0.38x10(8) (n=17) and TChigh=15.8+/-2.38x10(8) (n=18) (P<0.001). A directional fractal curve was generated for each image, and image texture was characterized by directional fractal curve parameters. Elastin volume fraction and interlamellar distance were obtained by image analysis. Wall stress distribution was determined from a finite element model of the arterial wall with multiple layers simulating elastin lamellae. DFC amplitude was related to elastin volume fraction. Increased TC (TClow versus TChigh) was associated with lower directional fractal curve amplitude (0.23+/-0.02 versus 0.14+/-0.02; P<0.001), reduced elastin volume fraction (36.5+2.6% versus 25.7+2.1%; P<0.01), and increased interlamellar distance (8.5+/-0.5 versus 11.5+/-1.0 microm; P<0.05). Loss of medial elastic function increased pressure-dependent maximal circumferential stress. Structural alterations of medial elastin, quantified by fractal parameters, are associated with cumulative effects of repeated pulsations due to the combined contribution of age and heart rate. Loss of medial functional elasticity increases luminal wall stress, increasing the possibility of endothelial damage and predisposition to atherosclerosis.
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PMID:Quantification of alterations in structure and function of elastin in the arterial media. 967 56

Atherosclerosis is clearly one of the most life-threatening diseases and a major cause of morbidity and mortality in industrialized countries. Typical arterial lesions contain both cells originating from the blood (monocytes/macrophages) and locally-recruited smooth muscle cells. The structure of the artery is profoundly disrupted. Degradation of arterial elastin fibers results in loss of elasticity, and several elastin peptides are released that can interact with various cells via an increasingly well-characterized elastin receptor. Elastin receptor-mediated reactions that are of obvious physiologic importance include vasodilating effects and induction of mesenchymal cell adhesion to elastin fibers. Other effects are potentially harmful, such as increased elastase production, free radical release, induction of LDL oxidation, and stimulation of endogenous cholesterol production. These deleterious effects become predominant during aging as a result of chronic exposure of the elastin receptor to circulating elastin peptides. This review describes the results of recent investigations into the biological effects of elastin peptides.
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PMID:Biological effects of elastin peptides. 984 68

Elastin, an abundant structural protein present in the arterial wall, is prone to calcification in a number of disease processes including porcine bioprosthetic heart valve calcification and atherosclerosis. The mechanisms of elastin calcification are not completely elucidated. In the present work, we demonstrated calcification of purified elastin in rat subdermal implants (Ca(2+) = 89.73 +/- 9.84 microgram/mg after 21 days versus control, unimplanted Ca(2+) = 0.16 +/- 0.04 microgram/mg). X-ray diffraction analysis along with resolution enhanced FTIR spectroscopy demonstrated the mineral phase to be a poorly crystalline hydroxyapatite. We investigated the time course of calcification, the effect of glutaraldehyde crosslinking on calcification, and mechanisms of inhibition of elastin calcification by pretreatment with aluminum chloride (AlCl(3)). Glutaraldehyde pretreatment did not affect calcification (Ca(2+) = 89.06 +/- 17.93 microgram/mg for glutaraldehyde crosslinked elastin versus Ca(2+) = 89.73 +/- 9.84 microgram/mg for uncrosslinked elastin). This may be explained by radioactive ((3)H) glutaraldehyde studies showing very low reactivity between glutaraldehyde and elastin. Our results further demonstrated that AlCl(3) pretreatment of elastin led to complete inhibition of elastin calcification using 21-day rat subdermal implants, irrespective of glutaraldehyde crosslinking (Ca(2+) = 0.73-2.15 microgram/mg for AlCl(3) pretreated elastin versus 89.73 +/- 9.84 for untreated elastin). The AlCl(3) pretreatment caused irreversible binding of aluminum ions to elastin, as assessed by atomic emission spectroscopy. Moreover, aluminum ion binding altered the spatial configuration of elastin as shown by circular dichroism (CD), Fourier transform infrared (FTIR), and (13)C nuclear magnetic resonance (NMR) spectroscopy studies, suggesting a net structural change including a reduction in the extent of beta sheet structures and an increase in coil-turn conformations. Thus, it is concluded that purified elastin calcifies in rat subdermal implants, and that the AlCl(3)-pretreated elastin completely resists calcification due to irreversible aluminum ion binding and subsequent structural alterations caused by AlCl(3).
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PMID:Elastin calcification and its prevention with aluminum chloride pretreatment. 1048 55

Elastin, a major extracellular matrix protein present in arterial walls provides elastic recoil and resilience to arteries. Elastin is prone to calcification in a number of cardiovascular diseases including atherosclerosis and bioprosthetic heart valve mineralization. We have recently shown that purified elastin when implanted subdermally in rats undergoes severe calcification. In the present study, we used this elastin implant model to investigate the molecular mechanisms underlying elastin calcification. Intense matrix metalloproteinase (MMP-2) and tenascin-C (TN-C) expression were seen in the proximity of the initial cal-cific deposits at 7 days. Gelatin zymography studies showed both MMP-2 (latent and active form) and MMP-9 expression within the implants. To investigate the role of MMPs in calcification, rats were administered a MMP inhibitor, (2S:-allyl-N:-hydroxy-3R:-isobutyl-N:-(1S:-methylcarbamoyl-2-ph enylet hyl)-succinamide (BB-1101) by daily injection, either systemically or at the implant site. The site-specific BB-1101 administration almost completely suppressed TN-C expression, as shown by immunohistochemical staining, within the implants. The systemic BB-1101 injections also significantly reduced TN-C expression within the elastin implants. Moreover, calcification of elastin implants was significantly reduced in the site-specific administration group (5.43 +/- 1.03 microg/mg Ca for BB-1101 group versus 21.71 +/- 1.19 for control group, P: < 0.001). Alizarin Red staining clearly showed that the elastin fibers were heavily calcified in the control group, whereas in BB-1101 group the calcification was scarce with few fibers showing initial calcification deposits. The systemic administration of BB-1101 also significantly reduced elastin calcification (28.07 +/- 5.81 control versus 16.92 +/- 2.56 in the BB-1101 group, P: < 0.05), although less than the site-specific administration. Thus, the present studies indicate that MMPs and TN-C play a role in elastin-oriented calcification.
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PMID:Inhibition of matrix metalloproteinase activity attenuates tenascin-C production and calcification of implanted purified elastin in rats. 1098 Jan 28

Abdominal aortic aneurysms and their management remain a significant health problem that is likely to assume greater importance with the expansion of the elderly population. Elastin fibres degradation and extracellular matrix remodelling seems to be the basic process in aneurysm formation. Recent investigations revealed the principal role of elastin-laminin receptor in extracellular matrix remodelling in aging and atherosclerosis. The correlation between events observed in animal aneurysm models, human aneurysms and in experiments on elastin-laminin receptor properties was discussed to propose the hypothesis about the role of elastin peptides and elastin-laminin receptor in aortic aneurysm formation.
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PMID:Elastin-laminin receptor and abdominal aortic aneurysms. New subject to study? A review. 1142 69

Elastin is a major component of the extracellular matrix. Elastin peptides derived from its degradation are present in human sera. Elastin peptides induce on fibroblasts, phagocytic cells, lymphocytes, smooth muscle cells and endothelial cells, a variety of biological effects mediated by the elastin-laminin receptor which has been demonstrated to be present on the membrane of these cells. The transduction pathway of the ELR receptor involves the activation of phospholipase C (PLC) by a pertussis toxin sensitive G-protein. PLC induces the production of inositol trisphosphate (IP3) leading to the increase of the intracellular free calcium on one hand, and of diacylglycerol (DAG) which stimulates the translocation to the membrane of PKC leading to the phosphorylation of members of the MAPK family, such as p42/p44 MAPK. Considering the multiple biological effects of ELR the elucidation of the complexity of the signaling pathways will help to better modulate it, mainly in pathological situations such as atherosclerosis.
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PMID:[The elastin-laminin receptor]. 1172 28

Heart disease is directly associated with aging as well as progression of atherosclerosis. The vessels begin to stiffen with age. It is speculated that the increase in stiffness can occur as a result of either increase progression of atherosclerosis or possibly due to the deterioration of the elastic components of the arterial wall. Regardless of the mechanism, an increase in vessel stiffness can lead to significant increase in the pathophysiological progression of the disease. The overall objectives of this investigation were to evaluate the coronary artery obtained from cadavers in their 7th, 8th and 9th of life and characterized the level of atherosclerosis and to identify using special elastin staining techniques the involvement of fiber disruption in atherosclerosis. The coronary arteries were obtained from cadaveric donors at the University of Saskatoon (average age 81.7 years, range 77-92 years of age). The arteries were fixed, sectioned and stained for routine analysis as well as with an Elastin staining protocol. The arteries were screened and the level of atherosclerosis was measured as well as thickness changes within the arteries. Digital imaging was used to capture the areas of elastin disruption. The overall results suggest elastin disruption occurs as the atherosclerotic plaque progresses. The imaging system in conjunction with elastin staining allows for a very sensitive method to analyze the tissue for the progression of pathophysiological disease mechanisms.
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PMID:The use of digital imaging technology to assess the pathogenesis of coronary atherosclerosis: the role of elastin. 1272 31

The matrix-degrading activity of several proteases are involved in the accelerated breakdown of extracellular matrix associated with vascular remodeling during the development of atherosclerosis and vascular injury-induced neointimal formation. Previous studies have shown that the potent elastolytic cysteine proteases, cathepsins S and K, are overexpressed in atherosclerotic lesions in human and animal models. However, the role of these cathepsins in vascular remodeling remains unclear. In the present study, the expressions of cathepsin S and K and their inhibitor cystatin C were examined during arterial remodeling using a rat carotid artery balloon-injury model. The increase in both cathepsin S and K mRNA levels was observed from day 1 and day 3 through day 14 following the induction of balloon injury, respectively. Western blotting analysis revealed that both cathepsin S and K protein levels also increased in the carotid arteries during neointima formation, coinciding with an increase elastolytic activity assayed using Elastin-Congo red, whereas, no significant change in the expressions of cystatin C mRNA and protein was observed during follow-up periods after injury. Immunohistochemistry, Western blot, and in situ hybridization showed that the increase of cathepins S and K and the decrease of cystatin C occurred preferentially in the developing neointima. These findings suggest that cathepsin S and K may participate in the pathological arterial remodeling associated with restenosis.
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PMID:Increased expression of elastolytic cysteine proteases, cathepsins S and K, in the neointima of balloon-injured rat carotid arteries. 1469 37

Elastin degeneration and calcification occur in many cardiovascular diseases, including medial arterial elastocalcinosis, atherosclerosis, and bioprosthetic heart valve mineralization. In the present study, we tested the hypothesis that the onset and progression of elastin-oriented calcification is associated with matrix remodeling and elastin degradation events. We studied whether aluminum ions inhibit elastin calcification by reducing elastin degradation and altering remodeling events. Subdermal implantation of pure elastin in juvenile rats resulted in a time-dependent calcification of elastin, reaching high levels 21 days after implantation. In situ hybridization showed that elastin calcification was associated with an up-regulation of matrix metalloproteinase (MMP) mRNA expression, specifically MMP-9 and MMP-2. Gelatin zymography demonstrated increased MMP-9 and MMP-2 enzyme activities in early stages of elastin calcification. Calcified elastin displayed a time-dependent pattern of tenascin-C (TN-C) and alkaline phosphatase (AP) expression. Pretreatment of pure elastin with aluminum ions prior to implantation resulted in complete inhibition of elastin calcification. Aluminum ion binding to elastin was found to protect elastin against MMP-mediated degradation in vitro. Noncalcified, explanted aluminum-pretreated elastin exhibited reduced activities of MMPs. TN-C expression in elastin implants exhibited a time-dependent pattern that was also affected by pretreatment of elastin with aluminum ions. In conclusion, elastin calcification is accompanied by matrix remodeling events, and the efficacy of aluminum pretreatment in inhibiting elastin calcification may be related in part to its effects on elastin remodeling.
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PMID:Involvement of matrix metalloproteinases and tenascin-C in elastin calcification. 1508 71


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