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Journal ArticleDOI

Elastic fiber homeostasis requires lysyl oxidase-like 1 protein.

TL;DR: It is shown that mice lacking the protein lysyl oxidase–like 1 (LOXL1) do not deposit normal elastic fibers in the uterine tract post partum and develop pelvic organ prolapse, enlarged airspaces of the lung, loose skin and vascular abnormalities with concomitant tropoelastin accumulation.
Abstract: Elastic fibers are components of the extracellular matrix and confer resilience1. Once laid down, they are thought to remain stable2, except in the uterine tract where cycles of active remodeling occur3. Loss of elastic fibers underlies connective tissue aging and important diseases including emphysema4,5,6,7. Failure to maintain elastic fibers is explained by a theory of antielastase-elastase imbalance8, but little is known about the role of renewal. Here we show that mice lacking the protein lysyl oxidase–like 1 (LOXL1) do not deposit normal elastic fibers in the uterine tract post partum and develop pelvic organ prolapse, enlarged airspaces of the lung, loose skin and vascular abnormalities with concomitant tropoelastin accumulation. Distinct from the prototypic lysyl oxidase (LOX), LOXL1 localizes specifically to sites of elastogenesis and interacts with fibulin-5. 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.

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Citations
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Journal ArticleDOI
TL;DR: By correlating vessel mechanics with physiological blood pressure across animal species and in mice with altered vessel compliance, it is shown that cardiac and vascular development are physiologically coupled, and there is evidence for a universal elastic modulus that controls the parameters of ECM deposition in vessel wall development.
Abstract: An important factor in the transition from an open to a closed circulatory system was a change in vessel wall structure and composition that enabled the large arteries to store and release energy during the cardiac cycle. The component of the arterial wall in vertebrates that accounts for these properties is the elastic fiber network organized by medial smooth muscle. Beginning with the onset of pulsatile blood flow in the developing aorta, smooth muscle cells in the vessel wall produce a complex extracellular matrix (ECM) that will ultimately define the mechanical properties that are critical for proper function of the adult vascular system. This review discusses the structural ECM proteins in the vertebrate aortic wall and will explore how the choice of ECM components has changed through evolution as the cardiovascular system became more advanced and pulse pressure increased. By correlating vessel mechanics with physiological blood pressure across animal species and in mice with altered vessel compliance, we show that cardiac and vascular development are physiologically coupled, and we provide evidence for a universal elastic modulus that controls the parameters of ECM deposition in vessel wall development. We also discuss mechanical models that can be used to design better tissue-engineered vessels and to test the efficacy of clinical treatments.

865 citations


Cites background from "Elastic fiber homeostasis requires ..."

  • ...LOXL1 has been shown to interact with fibulin-5 (170) and to interact genetically with fibrillin-2 (79)....

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  • ...However, postpartum Loxl1 / mice show fragmented elastic fibers, suggesting a role for LOXL1 in elastic fiber maintenance (170)....

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Journal ArticleDOI
07 Sep 2007-Science
TL;DR: Two nonsynonymous SNPs in exon 1 of the gene LOXL1 explain the association with glaucoma, and the data suggest that they confer risk of XFG mainly through exfoliation syndrome (XFS).
Abstract: Glaucoma is a leading cause of irreversible blindness A genome-wide search yielded multiple single-nucleotide polymorphisms (SNPs) in the 15q241 region associated with glaucoma Further investigation revealed that the association is confined to exfoliation glaucoma (XFG) Two nonsynonymous SNPs in exon 1 of the gene LOXL1 explain the association, and the data suggest that they confer risk of XFG mainly through exfoliation syndrome (XFS) About 25% of the general population is homozygous for the highest-risk haplotype, and their risk of suffering from XFG is more than 100 times that of individuals carrying only low-risk haplotypes The population-attributable risk is more than 99% The product of LOXL1 catalyzes the formation of elastin fibers found to be a major component of the lesions in XFG

654 citations

Journal ArticleDOI
TL;DR: In addition to elastin and collagen, LOX can oxidize lysine within a variety of cationic proteins, suggesting that its functions extend beyond its role in the stabilization of the extracellular matrix.
Abstract: Lysyl oxidase (LOX) oxidizes the side chain of peptidyl lysine converting specific lysine residues to residues of α-aminoadipic-δ-semialdehyde. This posttranslational chemical change permits the covalent crosslinking of the component chains of collagen and those of elastin, thus stabilizing the fibrous deposits of these proteins in the extracellular matrix. Four LOX-like (LOXL) proteins with varying degrees of similarity to LOX have been described, constituting a family of related proteins. LOX is synthesized as a preproprotein which emerges from the cell as proLOX and then is processed to the active enzyme by proteolysis. In addition to elastin and collagen, LOX can oxidize lysine within a variety of cationic proteins, suggesting that its functions extend beyond its role in the stabilization of the extracellular matrix. Indeed, recent findings reveal that LOX and LOXL proteins markedly influence cell behavior including chemotactic responses, proliferation, and shifts between the normal and malignant phenotypes.

529 citations

Journal ArticleDOI
TL;DR: The authors provide an updated insight into the molecular and cellular pathobiology of COPD based on human and/or animal data.
Abstract: Chronic obstructive pulmonary diseases (COPD), comprised of pulmonary emphysema, chronic bronchitis, and structural and inflammatory changes of small airways, is a leading cause of morbidity and mortality in the world. A better understanding of the pathobiology of COPD is critical for the developing of novel therapies, as the majority of patients with the disease have little therapeutic options at the present time. The pathobiology of COPD encompasses multiple injurious processes including inflammation (excessive or inappropriate innate and adaptive immunity), cellular apoptosis, altered cellular and molecular alveolar maintenance program, abnormal cell repair, extracellular matrix destruction (protease and anti-protease imbalance), and oxidative stress (oxidant and antioxidant imbalance). These processes are triggered by urban and rural air pollutants and active and/or passive cigarette smoke and modified by cellular senescence and infection. A series of receptor-mediated signal transduction pathways are activated by reactive oxygen species and tobacco components, resulting in impairment of a variety of cell signaling and cytokine networks, subsequently leading to chronic airway responses with mucus production, airway remodeling, and alveolar destruction. The authors provide an updated insight into the molecular and cellular pathobiology of COPD based on human and/or animal data.

488 citations


Cites background from "Elastic fiber homeostasis requires ..."

  • ...Lysyl oxidase-like protein 1-deficient mice did not deposit normal elastic fiber and showed early onset of emphysema (190)....

    [...]

Journal ArticleDOI
TL;DR: The mechanisms of chronic obstructive pulmonary disease may be heterogeneous, according to severity, and clinical phenotypes need to be correlated with cellular and pathological processes, and treatments may be targeted to patients with specific mechanisms.
Abstract: Chronic obstructive pulmonary disease is a leading global cause of morbidity and mortality that is characterised by inexorable deterioration of small airways obstruction with emphysema associated with cellular inflammation and structural remodelling. Other features include apoptosis as well as proliferation of cells, and both tissue repair and lack of tissue repair. Metalloprotease release, together with that of apoptotic factors, may underlie the emphysema, and, conversely, fibrosis of the small airways may be accounted for by the effects of growth factor activation. In advanced disease, influential factors include the development of autoimmunity, with activation of dendritic cells and T-helper cells of both type 1 and 2, and the senescence response. An inability of macrophages to ingest apoptosed cells and bacteria may exacerbate inflammatory responses. Systemic inflammation with concomitant cardiovascular disease and metabolic syndrome may reflect the effect of cigarette smoke on nonpulmonary cells. Corticosteroid resistance may be secondary to oxidative stress mechanisms, such as inactivation of histone deacetylases. The mechanisms of chronic obstructive pulmonary disease may be heterogeneous, according to severity, and clinical phenotypes need to be correlated with cellular and pathological processes. Treatments may be targeted to patients with specific mechanisms.

479 citations

References
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Journal ArticleDOI
26 Sep 1997-Science
TL;DR: Smoke-exposed MME-/- mice that received monthly intratracheal instillations of monocyte chemoattractant protein-1 showed accumulation of alveolar macrophages but did not develop air space enlargement, indicating that macrophage elastase is probably sufficient for the development of emphysema that results from chronic inhalation of cigarette smoke.
Abstract: To determine which proteinases are responsible for the lung destruction characteristic of pulmonary emphysema, macrophage elastase–deficient (MME −/− ) mice were subjected to cigarette smoke. In contrast to wild-type mice, MME − / − mice did not have increased numbers of macrophages in their lungs and did not develop emphysema in response to long-term exposure to cigarette smoke. Smoke-exposed MME − / − mice that received monthly intratracheal instillations of monocyte chemoattractant protein–1 showed accumulation of alveolar macrophages but did not develop air space enlargement. Thus, macrophage elastase is probably sufficient for the development of emphysema that results from chronic inhalation of cigarette smoke.

1,434 citations

Journal ArticleDOI
H. Kagan1, Wande Li1
TL;DR: Although the three‐dimensional structure of LO has yet to be determined, the present treatise offers hypotheses based upon its primary sequence, which may underlie the prominent electrostatic component of its unusual substrate specificity as well as the catalysis‐suppressing function of the propeptide domain of prolysyl oxidase.
Abstract: Lysyl oxidase (LO) plays a critical role in the formation and repair of the extracellular matrix (ECM) by oxidizing lysine residues in elastin and collagen, thereby initiating the formation of covalent crosslinkages which stabilize these fibrous proteins. Its catalytic activity depends upon both its copper cofactor and a unique carbonyl cofactor and has been shown to extend to a variety of basic globular proteins, including histone H1. Although the three-dimensional structure of LO has yet to be determined, the present treatise offers hypotheses based upon its primary sequence, which may underlie the prominent electrostatic component of its unusual substrate specificity as well as the catalysis-suppressing function of the propeptide domain of prolysyl oxidase. Recent studies have demonstrated that LO appears to function within the cell in a manner, which strongly modifies cellular activity. Newly discovered LO-like proteins also likely play unique roles in biology. © 2002 Wiley-Liss, Inc.

872 citations

Journal ArticleDOI
10 Jan 2002-Nature
TL;DR: It is reported that fibulin-5 (also known as DANCE), a recently discovered integrin ligand, is an essential determinant of elastic fibre organization and may provide anchorage of elastic fibres to cells, thereby acting to stabilize and organize elastic fibre in the skin, lung and vasculature.
Abstract: The elastic fibre system has a principal role in the structure and function of various types of organs that require elasticity, such as large arteries, lung and skin1,2. Although elastic fibres are known to be composed of microfibril proteins (for example, fibrillins and latent transforming growth factor (TGF)-β-binding proteins) and polymerized elastin, the mechanism of their assembly and development is not well understood. Here we report that fibulin-5 (also known as DANCE), a recently discovered integrin ligand3, is an essential determinant of elastic fibre organization. fibulin-5-/- mice generated by gene targeting exhibit a severely disorganized elastic fibre system throughout the body. fibulin-5-/- mice survive to adulthood, but have a tortuous aorta with loss of compliance, severe emphysema, and loose skin (cutis laxa). These tissues contain fragmented elastin without an increase of elastase activity, indicating defective development of elastic fibres. Fibulin-5 interacts directly with elastic fibres in vitro, and serves as a ligand for cell surface integrins αvβ3, αvβ5 and α9β1 through its amino-terminal domain. Thus, fibulin-5 may provide anchorage of elastic fibres to cells, thereby acting to stabilize and organize elastic fibres in the skin, lung and vasculature.

594 citations

Journal ArticleDOI
TL;DR: Evidence is provided for the hypothesis that pudendal neuropathy due to vaginal delivery persists and may worsen with time and for the effect of childbirth on the pelvic floor striated sphincter musculature.
Abstract: We have studied the pelvic floor musculature and its innervation in 14 of 24 (58 per cent) multiparous women who had been recruited into a study of the effect of childbirth on the pelvic floor as part of a prospective investigation that began in 1983. These 24 women had all delivered by the vaginal route without forceps assistance. Five of the 14 had developed clinical symptoms of stress incontinence 5 years later; two of them had had a further uncomplicated vaginal delivery during this time. There was manometric and neurophysiological evidence of weakness because of partial denervation of the pelvic floor striated sphincter musculature, with pudendal neuropathy, which was more marked in those women with incontinence. These findings provide direct evidence for the hypothesis that pudendal neuropathy due to vaginal delivery persists and may worsen with time.

583 citations

Journal ArticleDOI
10 Jan 2002-Nature
TL;DR: Fibulin-5-/- mice develop marked elastinopathy owing to the disorganization of elastic fibres, with resulting loose skin, vascular abnormalities and emphysematous lung, which resembles the cutis laxa syndrome in humans.
Abstract: Extracellular elastic fibres provide mechanical elasticity to tissues and contribute towards the processes of organ remodelling by affecting cell-cell signalling. The formation of elastic fibres requires the assembly and crosslinking of tropoelastin monomers, and organization of the resulting insoluble elastin matrix into functional fibres. The molecules and mechanisms involved in this process are unknown. Fibulin-5 (also known as EVEC/DANCE) is an extracellular matrix protein abundantly expressed in great vessels and cardiac valves during embryogenesis, and in many adult tissues including the aorta, lung, uterus and skin, all of which contain abundant elastic fibres. Here we show that fibulin-5 is a calcium-dependent, elastin-binding protein that localizes to the surface of elastic fibres in vivo. fibulin-5-/- mice develop marked elastinopathy owing to the disorganization of elastic fibres, with resulting loose skin, vascular abnormalities and emphysematous lung. This phenotype, which resembles the cutis laxa syndrome in humans, reveals a critical function for fibulin-5 as a scaffold protein that organizes and links elastic fibres to cells. This function may be mediated by the RGD motif in fibulin-5, which binds to cell surface integrins, and the Ca2+-binding epidermal growth factor (EGF) repeats, which bind elastin.

570 citations

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