Disease relevance of Eln

• Levels of tropoelastin mRNA and protein were lower in aortas and isolated SMCs of adult transgenic mice expressing the human B-myb gene, driven by the basal cytomegalovirus promoter, compared with age-matched wild type (WT) animals [1].
• The pathogenesis of aneurysm formation was studied in Blotchy (Blo) mice which have a hereditary defect in collagen and elastin cross-linking [2].
• The most upregulated gene in the smoke group, MMP12, is a matrix metalloproteinase that preferentially degrades elastin and has been implicated in COPD development [3].
• Supravalvular aortic stenosis is an autosomal-dominant disease of elastin (Eln) insufficiency caused by loss-of-function mutations or gene deletion [4].
• However, lack of elastin is not associated with endothelial damage, thrombosis or inflammation, which occur in models of atherosclerosis [5].

High impact information on Eln

• Thus elastin polymer deposition is a crucial aspect of elastic fiber maintenance and is dependent on LOXL1, which serves both as a cross-linking enzyme and an element of the scaffold to ensure spatially defined deposition of elastin [6].
• Through a global analysis of pulmonary gene expression in the lungs of mice lacking this integrin (Itgb6 null mice) we have identified a marked induction of macrophage metalloelastase (Mmp12)--a metalloproteinase that preferentially degrades elastin and has been implicated in the chronic lung disease emphysema [7].
• Although elastic fibres are known to be composed of microfibril proteins (for example, fibrillins and latent transforming growth factor (TGF)-beta-binding proteins) and polymerized elastin, the mechanism of their assembly and development is not well understood [8].
• Disruption of elastin is enough to induce subendothelial proliferation of smooth muscle and may contribute to obstructive arterial disease [5].
• 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 [5].

Chemical compound and disease context of Eln

• Chemotaxis of the M27 variant of Lewis lung carcinoma to VGVAPG, an elastin-derived chemoattractant, is restricted by the basement membrane glycoprotein laminin [9].
• Obvious in areas of fibrosis, elastin mRNA expression was occasionally increased in the pleura and airway wall 7 days after bleomycin treatment; alpha 1(I) collagen mRNA expression was generally stronger than elastin mRNA expression in areas of fibrosis and was frequently intense in the adventitia of airways and associated blood vessels [10].
• In this study, we examined steady-state elastin mRNA levels after lung injury in the mouse induced by (1) butylated hydroxytoluene (BHT) which causes acute lung injury with recovery, (2) BHT + 70% O2 (fibrosis), or (3) 70% O2 [11].
• The cysteinyl protease inhibitor E64d limits this increased elastolysis, indicating involvement of cysteine proteases in elastin degradation during atherogenesis [12].

Biological context of Eln

• B-Myb represses elastin gene expression in aortic smooth muscle cells [1].
• The temporal relationship between LOX mRNA and protein, processing of LOXL1 protein, FBLN5 and tropoelastin protein, and desmosine content in the vagina suggest that a burst of elastic fiber assembly and cross linking occurs in the vaginal wall postpartum [13].
• Whereas tropoelastin mRNA levels rose during embryogenesis and were the highest in neonatal mice, Abcc6 mRNA levels remained constantly low throughout embryogenesis [14].
• Normal wound healing in mice deficient for fibulin-5, an elastin binding protein essential for dermal elastic fiber assembly [15].
• Neb and Eln are linked neither to each other nor to any other marker on proximal mouse chromosome 1 [16].

Anatomical context of Eln

• Tropoelastin mRNA expression in aortas of 6-day-old neonatal transgenic and WT animals was comparable [1].
• The level of elastin mRNA transcripts was also markedly lower in both cell lines in comparison to controls [17].
• We report that fibulin-5 protein potently induces elastic fiber assembly and maturation by organizing tropoelastin and cross-linking enzymes onto microfibrils [18].
• Our results indicate that fibulin-5 is coordinately expressed and regulated with elastin in lung fibroblasts and may serve a key role during lung injury and repair [19].
• The chemotactic response was significantly diminished by pretreatment of macrophages with lactose or with the elastin-derived peptide VGVAPG and by pretreatment of samples with a monoclonal antibody directed against an EBP recognition sequence [20].

Associations of Eln with chemical compounds

• Collectively, these data support a model whereby the elastin gene product, signaling through the VGVAPG domain, directly induces VSMC myofibrillogenesis [21].
• Previous studies have established that cross-links in collagen and elastin are decreased in these animals due to impaired formation of lysine-derived aldehydes [22].
• A quantitative slot-blot immunobinding assay showed that tretinoin induced a threefold higher amount of tropoelastin compared with controls [23].
• Lysyl oxidase activity in biological samples is traditionally and most reliably assessed by tritium release end-point assays using radiolabeled collagen or elastin substrates involving laborious vacuum distillation of the released tritiated water [24].
• There was a 147% increase in insoluble elastin with propranolol and a lesser increase of 54% in insoluble collagen [25].

Enzymatic interactions of Eln

• Lysyl oxidase catalyzes oxidative deamination of peptidyl-lysine and hydroxylysine residues in collagens and lysine residues in elastin to form peptidyl aldehydes that are required for the formation of covalent cross-links in normal extracellular matrix biosynthesis [26].

Co-localisations of Eln

• LTBP-2 colocalized with tropoelastin within the perichondrium, lung, dermis, large arterial vessels, epicardium, pericardium, and heart valves at various stages of rodent embryonic development [27].

Regulatory relationships of Eln

• Expression of an autoactivating form of MMP-9 in macrophages in vitro greatly enhances elastin degradation and induces significant plaque disruption when overexpressed by macrophages in advanced atherosclerotic lesions of apoE-/- mice in vivo [28].
• Our studies show that fibulin-1 is expressed surrounding the primordial VSMCs of the vessel wall before elastin precursors are present and suggest that differential expression of the JB3 antigen (Wunsch et al., 1994) may be indicative of early diversity among embryonic VSMCs [29].
• Pharmacological modulation of the antioxidant enzymes activities and the concentration of peroxidation products in fibroblasts stimulated with elastin peptides [30].

Other interactions of Eln

• The linkage and genetic distances between Eln and the closest molecular markers used in this study are centromere-D5Mit95, D5Mit96-6.7 cM-Gus, Eln-4.0 cM-Zp3-telomere [31].
• The authors systematically analysed the expression of elastin; collagen types I, III, IV; laminin; and fibronectin during mouse detrusor muscle development, a period during which downregulation of detrusor proliferation and increasing smooth muscle differentiation is known to occur [32].
• CONCLUSIONS: Our findings demonstrate that aortic extracts from mgR/mgR mice can stimulate macrophage chemotaxis by interaction with EBP and show that a fibrillin-1 fragment possesses chemotactic stimulatory activity similar to that of elastin degradation peptides [20].
• Specifically, levels of elastin and glycosoaminoglycans are increased, collagen fibers are more compactly organized, and matrix modulators like integrins, TGFbeta1, and matrix metalloproteinases (MMPs) are altered both basally and after wounding in Smad3 knockout mice [33].
• We studied the expression of LTBP-2 in the developing mouse and rat by in situ hybridization, using tropoelastin expression as a marker of tissues participating in elastic fiber formation [27].

Analytical, diagnostic and therapeutic context of Eln

• Since elastin deposition occurs early in development, microarray analysis was performed using nontransgenic mice [1].
• Immunofluorescence studies localized both enzymes to elastin at the earliest stages of elastic fiber assembly [34].
• The complete coding sequence for mouse tropoelastin was obtained from overlapping reverse transcriptase polymerase chain reaction (PCR) amplimers [31].
• Electron microscopy revealed that the elastin aggregates are highly unusual in that they contain evenly distributed rod-like filaments, in contrast to the amorphous appearance of normal elastic fibers [35].
• These data indicate that plasmin proteolysis plays a major role in allograft arteriosclerosis by mediating elastin degradation, macrophage infiltration, media remodeling, medial smooth muscle cell migration, and formation of a neointima [36].

References