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PubMed1997

Elastin degradation by matrix metalloproteinases. Cleavage site specificity and mechanisms of elastolysis.

Insoluble elastin was used as a substrate to characterize the peptide bond specificities of human (HME) and mouse macrophage elastase (MME) and to compare these enzymes with other mammalian metalloproteinases and serine elastases. New amino termini detected by protein sequence analysis in insoluble elastin following proteolytic digestion reveal the P'1 residues in the carboxyl-terminal direction from the scissile bond. The relative proportion of each amino acid in this position reflects the proteolytic preference of the elastolytic enzyme. The predominant amino acids detected by protein sequence analysis following cleavage of insoluble elastin with HME, MME, and 92-kDa gelatinase were Leu, Ile, Ala, Gly, and Val. HME and MME were similar in their substrate specificity and showed a stronger preference for Leu/Ile than did the 92-kDa enzyme. Fibroblast collagenase showed no activity toward elastin. The amino acid residues detected in insoluble elastin following hydrolysis with porcine pancreatic elastase and human neutrophil elastase were predominantly Gly and Ala, with lesser amounts of Val, Phe, Ile, and Leu. There were interesting specificity differences between the two enzymes, however. For both the serine and matrix metalloproteinases, catalysis of peptide bond cleavage in insoluble elastin was characterized by temperature effects and water requirements typical of common enzyme-catalyzed reactions, even those involving soluble substrates. In contrast to what has been observed for collagen, the energy requirements for elastolysis were not extraordinary, consistent with cleavage sites in elastin being readily accessible to enzymatic attack.

Amino Acid Sequence↗
PubMed1995

Modulation of elastin expression by heparin is dependent on the growth condition of vascular smooth muscle cells: up-regulation of elastin expression by heparin in the proliferating cells is mediated by the inhibition of protein kinase C activity.

The effect of heparin on elastin expression in the proliferating and quiescent phases of growth of smooth muscle cells was studied. Heparin stimulated elastin synthesis and its mRNA level 2-3 fold in the proliferating cells while it inhibited the cell proliferation. The inhibition of cell proliferation and the stimulation of elastin expression by heparin in the proliferating cells were mimicked by a potent protein kinase C antagonist, H-7, but not by H-89, W-7, and HA1004, suggesting that the effect of heparin is mediated by the inhibition of protein kinase C. In contrast, heparin inhibited elastin synthesis and its mRNA level slightly but exhibited no effect on cell proliferation in the growth-arrested cells. This result indicates that heparin reciprocally affects elastin expression depending on the growth state of smooth muscle cells. Heparin thus exerts a complex influence on elastin expression in smooth muscle cells.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1987

Developmental initiation of elastin gene expression by human fetal skin fibroblasts.

Elastin synthesis is initiated in many organs during the latter part of fetal development. By birth, accumulation of elastin in elastic fibers accounts in large part for the integrity and resilience of skin, blood vessels, and lungs. Developmental studies in several connective tissues of nonhuman vertebrates indicate that elastin synthesis is rapidly initiated during fetal life and that its expression is largely controlled by the abundance of its mRNA. Previous evidence for elastin synthesis in the developing human fetus has been derived from either histologic inference or studies of net accumulation. We now report that the developmental induction of cutaneous elastin synthesis appears to be stably reflected in cell culture. Production of elastin by human skin fibroblasts increased 7- to 14-fold between 17 and 19 weeks of gestation, reaching the levels found in neonatal skin fibroblasts. Consistent with other developmental studies, elastin synthesis was found to be under pretranslational control with relative mRNA levels increasing 6- to 15-fold by 19 weeks of gestation. Under the same circumstances, collagen expression and total protein synthesis were relatively constant among all strains examined. Human skin fibroblasts may thus be a useful system for examining developmentally regulated elastin gene expression.

Elastin↗
PubMed1993

Retinoic acid increases elastin in neonatal rat lung fibroblast cultures.

The factors that regulate elastin synthesis during pulmonary alveolar septal formation have not been identified. Because maximal alveolar elastin synthesis occurs over a relatively brief period (postnatal days 4-14 in the rat), we hypothesized that changes in the local concentrations of factors that regulate elastin synthesis may precede or accompany this period. Because pulmonary retinoid stores decline just before the fourth postnatal day, we also hypothesized that this decline could be accompanied by the utilization of retinoic acid, one of the most biologically active retinoids, in a regulatory process that increases elastin synthesis. If these hypotheses are correct, then retinoic acid should increase elastin synthesis by pulmonary cells. Therefore, cultures of neonatal rat lung fibroblasts were exposed to retinoic acid, and elastin production was quantitated. Retinoic acid produced a two- to threefold increase in the steady-state level of elastin mRNA, in soluble elastin, and in insoluble elastin. The transcriptional initiation rate of the elastin gene was 1.8-fold higher in nuclei that were isolated from retinoic acid-treated cells than in nuclei that were isolated from control cells. This indicates that the increase in steady-state elastin mRNA results, at least partially, from an increase in elastin transcription. Lung fibroblasts that were isolated from 8-day-old rats, but not cultured, contained retinoic acid. These findings suggest that retinoic acid is a potential regulator of elastin synthesis in developing pulmonary alveoli.

Animals↗
PubMed1997

Origin of extracellular matrix synthesis during coronary repair.

BACKGROUND: Coronary injury triggers differentiation of activated adventitial fibroblasts to myofibroblasts, which may contribute to neointimal formation and vascular remodeling. Accordingly, the purpose of this study was to examine the cellular origin of the enhanced synthesis of extracellular matrix proteins during coronary repair. METHODS AND RESULTS: The time course and localization of collagen and elastin expression were examined by in situ hybridization and immunohistochemistry in porcine coronary arteries after balloon-induced injury. Procollagen-alpha 1(I) transcripts and intracellular type I procollagen protein increased in the adventitia within 2 days after injury. This was followed by a sustained synthesis of type I procollagen in neointima beginning at 7 days and the extracellular accumulation of type I collagen in both layers. The origin of synthetic cells was further examined by colocalization of type I procollagen and bromodeoxyuridine labeling to activated adventitial cells, which translocated to neointima. Neointimal cells exhibited sustained synthetic activity manifested by the presence of type I procollagen and elastin at 3 months after injury. In contrast, the media showed only minor changes in the synthesis of collagen or elastin throughout coronary repair. CONCLUSIONS: Activated adventitial fibroblasts are endowed with synthetic capabilities after coronary injury. They express type I procollagen, with some of them translocating to the intima, where they continue to synthesize procollagen. The accumulation of type I collagen is evident in the adventitia and neointima, whereas elastin accumulates mainly in neointima. These findings support the involvement of adventitial fibroblasts in coronary repair and remodeling after endoluminal injury.

Angioplasty, Balloon↗
PubMed2001

Phenotypic alteration of vascular smooth muscle cells precedes elastolysis in a mouse model of Marfan syndrome.

Marfan syndrome is associated with early death due to aortic aneurysm. The condition is caused by mutations in the gene (FBN1) encoding fibrillin-1, a major constituent of extracellular microfibrils. Prior observations suggested that a deficiency of microfibrils causes failure of elastic fiber assembly during late fetal development. Mice homozygous for a targeted hypomorphic allele (mgR) of Fbn1 revealed a predictable sequence of abnormalities in the vessel wall including elastic fiber calcification, excessive deposition of matrix elements, elastolysis, and intimal hyperplasia. Here we describe previously unrecognized concordant findings in elastic vessels from patients with Marfan syndrome. Furthermore, ultrastructural analysis of mgR mice revealed cellular events that initiate destructive changes. The first detectable abnormality was an unusually smooth surface of elastic laminae, manifesting the loss of cell attachments that are normally mediated by fibrillin-1. Adjacent cells adopted alteration in their expression profile accompanied by morphological changes but retained expression of vascular smooth muscle cell markers. The abnormal synthetic repertoire of these morphologically abnormal smooth muscle cells in early vascular lesions included elastin, among other matrix elements, and matrix metalloproteinase 9, a known mediator of elastolysis. Ultimately, cell processes associated with zones of elastic fiber thinning and fragmentation. These data suggest that the loss of cell attachments signals a nonproductive program to synthesize and remodel an elastic matrix. This refined understanding of the pathogenesis of vascular disease in Marfan syndrome will facilitate the development of therapeutic strategies.

Actins↗
PubMed2000

Impaired distal airway development in mice lacking elastin.

Elastin is a major component of the mammalian lung, predominantly found in the alveoli. Destruction of alveolar elastic fibers is implicated in the pathogenic mechanism of emphysema in adults. These data define a role for elastin in the structure and function of the mature lung, and suggest that elastin is important for alveogenesis. To investigate the role of elastin in lung development, we examined mice lacking elastin (Eln-/-). At birth, the distal air sacs of Eln-/- lungs dilate to form abnormally large cavities. This phenotype appears before the synthesis and deposition of alveolar elastin, a process mediated by myofibroblasts and initiated after postnatal Day 4. Morphometric analyses demonstrate that the perinatal development of terminal airway branches is arrested in Eln-/- mice. The branching defect is accompanied by fewer distal air sacs that are dilated with attenuated tissue septae, a condition reminiscent of emphysema. Elastin expression in the lung parenchyma before alveogenesis is localized to the mesenchyme surrounding the developing airways, supporting a role for elastin in airway branching. Thus, in addition to its role in the structure and function of the mature lung, elastin is essential for pulmonary development and is important for terminal airway branching.

Actins↗
PubMed2002

Expression profiling of the developing mouse lung: insights into the establishment of the extracellular matrix.

We have undertaken a comprehensive gene expression profiling of the entire process of murine lung development using oligonucleotide-based microarrays. Our data reveals the expression pattern of approximately 11,000 genes throughout the morphologic stages of lung development. This includes known genes with unappreciated pulmonary expression and novel genes with undefined functions. Traditional gene expression analysis techniques verify a high degree of confidence in the microarray data. Examination of the data confirms previously known patterns of expression for extracellular matrix genes and provides new information regarding relationships in temporal expression among groups of these genes. Large-scale cluster analysis reveals associations in the expression profile of specific genes with defined developmental processes. For instance, we identify groups of genes, which are coordinately expressed with extracellular matrix genes during lung development. These data should serve as a resource for the pulmonary research community and assist in deciphering the molecular mechanisms governing normal lung development as well as those involved in aberrant developmental pathology.

Animals↗
PubMed2005

A functional mutation in the terminal exon of elastin in severe, early-onset chronic obstructive pulmonary disease.

We describe a novel variant in the terminal exon of human elastin, c.2318 G > A, resulting in an amino acid substitution of glycine 773 to aspartate (G773D) in a pedigree with severe early-onset chronic obstructive pulmonary disease (COPD). Transfection studies with elastin cDNAs demonstrate that the glycine to aspartate change compromises the ability of the mutant protein to undergo normal elastin assembly. Other functional consequences of this amino acid substitution include altered proteolytic susceptibility of the C-terminal region of elastin and reduced interaction of the exon 36 sequence with matrix receptors on cells. These results suggest that the G773D variant confers structural and functional consequences relevant to the pathogenesis of COPD.

Alternative Splicing↗
PubMed1995

Transforming growth factor-beta reverses a posttranscriptional defect in elastin synthesis in a cutis laxa skin fibroblast strain.

Skin fibroblasts from two cases of autosomal recessive cutis laxa (CL), having insignificant elastin production and mRNA levels, were challenged with transforming growth factor beta-1 (TGF-beta 1). Elastin production was brought from undetectable values to amounts typical of normal human skin fibroblasts in a dose-dependent fashion. Basic fibroblast growth factor (100 ng/ml) alone or in combination with TGF-beta 1 reduced elastin production and mRNA expression in CL skin fibroblasts more extensively than in normal cells. In situ hybridization showed that these effects were at the transcript level. One of the CL strains was examined in detail. Transcription rates for elastin were similar in normal and CL and unchanged by TGF-beta 1 or TGF-beta 2 (10 ng/ml), while in CL elastin mRNA half-life was increased > 10-fold by TGF-beta 2 and reduced 6-fold after TGF-beta 2 withdrawal, as compared with a control strain. Cycloheximide partially reversed elastin mRNA instability. These data are consistent with a defect in elastin mRNA stability that requires synthesis of labile factors or intact translational machinery, resulting in an extremely low steady state level of mRNA present in this strain of CL. Furthermore, TGF-beta can relieve elastin mRNA instability in at least one CL strain and elastin production defects in both CL strains.

Cells, Cultured↗
PubMed1995

A tissue-culture model for the study of canine vocal fold fibroblasts.

A tissue-culture model has been developed for the study of fibroblasts from the canine vocal fold. Laryngeal tissue (lamina propria) obtained from euthanized dogs is rinsed, cut into 1-mm3 pieces, and incubated in 5% carbon dioxide at 37 degrees C. A confluent monolayer is established within several days. Detectable levels of elastin in the tissue culture supernatant are measured by an indirect enzyme-linked immunosorbent assay. Various external agents have been shown to affect elastin production. The effects of KTP laser irradiation, hydrocortisone (1.3 mumol/L), transforming growth factor-beta (10 ng/mL), and human leukocyte elastase have been measured. Thus the canine vocal fold fibroblast tissue culture is established as a model for further investigations to improve wound healing and to understand the wound-healing process following laryngeal microsurgery.

Animals↗
PubMedDate not supplied

What is elastin; what is not.

Fibrous elastin is a biologic macromolecular construct for which there currently exists a wide disparity of descriptions. On the one hand is the view that elastin is an unambiguously random network of polypeptide chains best described functionally by analogy to rubber elasticity. On the other hand, elastin is viewed as being constructed of parallel aligned filaments that are due in large part to hydrophobic associations in an aqueous milieu and are comprised of describable, preferred conformations. One class of the conformations is elastomeric and gives rise to a proposed new mechanism of elasticity called the librational entropy mechanism of elasticity. While pertinent arguments of both perspectives are noted, this review presents the latter perspective. It begins with the century old delineation of two conditions of matter, colloids and crystalloids, making the point that biologic materials previously listed as colloidal (and as such considered to be without order) have one by one been described in terms of structures with beautiful regularities. Data on the primary structure of elastin and its cross-links are discussed as are electron microscopic studies on negatively stained fibrous elastin and coacervates of elastin peptides. It is demonstrated that conformational descriptions of repeating peptides of elastin can give rise to the filaments observed in the ultrastructural studies and to a three-component working model for a fundamental unit of elastin structure. It is argued that the dominant class of conformations in the three-component model are consistent with data on the thermodynamics of elasticity, on birefringence, and on chain mobility, which had previously been considered to be indicative only of random chains. The developing understandings of molecular conformation are shown to provide a basis with which to begin an understanding of the molecular pathology of elastin.

Amino Acid Sequence↗
PubMed1994

Nature and the multiple functions of the 67-kD elastin-/laminin binding protein.

Numerous cell types, including fibroblasts, vascular smooth muscle cells, chondroblasts, monocytes, neutrophils, and several tumor cells express the 67-kD galactolectin, homologous to the alternatively spliced variant of beta-galactosidase. The 67-kD protein resides on the cell surfaces and is capable of interacting with elastin, laminin and collagen type IV. This peripheral membrane protein binds its matrix ligands but only in the absence of galactosugars, whereas binding of galactosugar-containing moieties to its lectin site changes its molecular folding which causes discharge of the ligand and release of the receptor from the cell surface. This review will address the functional significance of the single receptor that interacts with multiple matrix proteins and can be shed from cell surfaces by galactosugars. I will emphasize the role of the 67-kD protein in divergent cellular processes, such as cell-matrix attachment, matrix assembly, cellular chemotaxis, and active migration through the vascular walls.

Alternative Splicing↗