Regulation of lysyl oxidase in vascular cells: lysyl oxidase as a new player in cardiovascular diseases

Rodrı́guez, Cristina; Martínez-González, José; Raposo, Berta; Alcudia, Javier F.; Guadall, Anna; Badimon, Lina

doi:10.1093/cvr/cvn102

Cited by 162 publications

(152 citation statements)

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“…The increase in collagen levels may reflect either increased collagen transcription or decreased collagen turnover, in response to hyperoxia. Along these lines, it is interesting to note that lysyl oxidases, which may act as scaffolding proteins in transcription factor complexes (26,55), have been reported to drive transcription of the col3a1 gene, encoding the collagen III ␣ 1 -subunit (18). As such, the elevated expression of lysyl oxidases may drive the elevated expression of collagens.…”

Section: Discussionmentioning

confidence: 99%

Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia

Mižíková

Ruiz‐Camp

Steenbock

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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RE. Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia. Am J Physiol Lung Cell Mol Physiol 308: L1145-L1158, 2015. First published April 3, 2015 doi:10.1152/ajplung.00039.2015.-Maturation of the lung extracellular matrix (ECM) plays an important role in the formation of alveolar gas exchange units. A key step in ECM maturation is cross-linking of collagen and elastin, which imparts stability and functionality to the ECM. During aberrant late lung development in bronchopulmonary dysplasia (BPD) patients and animal models of BPD, alveolarization is blocked, and the function of ECM cross-linking enzymes is deregulated, suggesting that perturbed ECM cross-linking may impact alveolarization. In a hyperoxia (85% O 2)-based mouse model of BPD, blunted alveolarization was accompanied by alterations to lung collagen and elastin levels and cross-linking. Total collagen levels were increased (by 63%). The abundance of dihydroxylysinonorleucine collagen cross-links and the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio were increased by 11 and 18%, respectively, suggestive of a profibrotic state. In contrast, insoluble elastin levels and the abundance of the elastin cross-links desmosine and isodesmosine in insoluble elastin were decreased by 35, 30, and 21%, respectively. The lung collagen-to-elastin ratio was threefold increased. Treatment of hyperoxia-exposed newborn mice with the lysyl oxidase inhibitor ␤-aminopropionitrile partially restored normal collagen levels, normalized the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio, partially normalized desmosine and isodesmosine cross-links in insoluble elastin, and partially restored elastin foci structure in the developing septa. However, ␤-aminopropionitrile administration concomitant with hyperoxia exposure did not improve alveolarization, evident from unchanged alveolar surface area and alveoli number, and worsened septal thickening (increased by 12%). These data demonstrate that collagen and elastin cross-linking are perturbed during the arrested alveolarization of developing mouse lungs exposed to hyperoxia. lung development; elastin; collagen; lysyl oxidase; alveolarization POSTNATAL LUNG DEVELOPMENT in mice is characterized by a period of intensive growth and remodeling of the lung parenchyma, which rapidly (over a period of days) generates a large number of small alveoli and thus maximizes the alveolar surface area over which gas exchange can take place. Secondary septation, the generation of new septa from preexisting septa, which then divide the air spaces, peaks in mice between 4 and 7 days after birth and is largely complete 21 days after birth. In humans, secondary septation is already well underway during late stages of pregnancy, and thus occurs in utero, and continues several years into postnatal life. Disturbances to the formation of secondary septa, such as the arrested secondary septation associated with bronchopulmonary dysplasia (BPD) in humans, leads to malformed lung...

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Section: Discussionmentioning

confidence: 99%

Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia

Mižíková

Ruiz‐Camp

Steenbock

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Strikingly, the potent effects of endotoxin on pulmonary vascular permeability can be prevented by manipulating ECM structure, and hence, this mechanical control pathway could potentially lead to new approaches to clinical therapy in the future, in addition to providing greater insight into how changes in pulmonary microvascular structure influence organ pathophysiology. Changes in LOX activity levels that alter tissue structure and ECM mechanics contribute to many pathological processes that are characterized by abnormal vascular permeability, including fibrotic disorders 33,39 and cancer progression 13,37 , as well as cardiovascular diseases 20,40,41 . Our results show that ECM mechanics need to be regulated tightly to maintain optimal cell-cell junctional integrity and pulmonary vascular function in normal lung.…”

Section: Discussionmentioning

confidence: 99%

Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics

et al. 2013

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Increased vascular permeability contributes to many diseases, including acute respiratory distress syndrome, cancer and inflammation. Most past work on vascular barrier function has focused on soluble regulators, such as tumour-necrosis factor-a. Here we show that lung vascular permeability is controlled mechanically by changes in extracellular matrix structure. Our studies reveal that pulmonary vascular leakage can be increased by altering extracellular matrix compliance in vitro and by manipulating lysyl oxidase-mediated collagen crosslinking in vivo. Either decreasing or increasing extracellular matrix stiffness relative to normal levels disrupts junctional integrity and increases vascular leakage. Importantly, endotoxin-induced increases of vascular permeability are accompanied by concomitant increases in extracellular matrix rigidity and lysyl oxidase activity, which can be prevented by inhibiting lysyl oxidase activity. The identification of lysyl oxidase and the extracellular matrix as critical regulators of lung vascular leakage might lead to the development of new therapeutic approaches for the treatment of pulmonary oedema and other diseases caused by abnormal vascular permeability.

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“…These processes would be impeded by an overstabilized ECM. Furthermore, Lox has already been implicated in several vascular pathologies (56) in which, when overexpressed, Lox can promote local neointimal thickening and vessel muscularization. These observations are interesting, because in addition to dysregulated angiogenesis, the pulmonary vasculature in patients with BPD undergoes remodeling that includes medial hypertrophy (thus, vessel thickening) and muscularization of small arteries.…”

Section: Discussionmentioning

confidence: 99%

Lysyl Oxidase Activity Is Dysregulated during Impaired Alveolarization of Mouse and Human Lungs

Kumarasamy¹,

Schmitt²,

Nave³

et al. 2009

Am J Respir Crit Care Med

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Rationale: Disordered extracellular matrix production is a feature of bronchopulmonary dysplasia (BPD). The basis of this phenomenon is not understood. Objectives: To assess lysyl oxidase expression and activity in the injured developing lungs of newborn mice and of prematurely born infants with BPD or at risk for BPD. Methods: Pulmonary lysyl oxidase and elastin gene and protein expression were assessed in newborn mice breathing 21 or 85% oxygen, in patients who died with BPD or were at risk for BPD, and in control patients. Signaling by transforming growth factor (TGF-b) was preemptively blocked in mice exposed to hyperoxia using TGFb-neutralizing antibodies. Lysyl oxidase promoter activity was assessed using plasmids containing the lox or loxl1 promoters fused upstream of the firefly luciferase gene. Measurements and Main Results: mRNA and protein levels and activity of lysyl oxidases (Lox, LoxL1, LoxL2) were elevated in the oxygeninjured lungs of newborn mice and infants with BPD or at risk for BPD. In oxygen-injured mouse lungs, increased TGF-b signaling drove aberrant lox, but not loxl1 or loxl2, expression. Lox expression was also increased in oxygen-injured fibroblasts and pulmonary artery smooth muscle cells. Conclusions: Lysyl oxidase expression and activity are dysregulated in BPD in injured developing mouse lungs and in prematurely born infants. In developing mouse lungs, aberrant TGF-b signaling dysregulated lysyl oxidase expression. These data support the postulate that excessive stabilization of the extracellular matrix by excessive lysyl oxidase activity might impede the normal matrix remodeling that is required for pulmonary alveolarization and thereby contribute to the pathological pulmonary features of BPD.

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Regulation of lysyl oxidase in vascular cells: lysyl oxidase as a new player in cardiovascular diseases

Cited by 162 publications

References 58 publications

Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia

Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia

Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics

Lysyl Oxidase Activity Is Dysregulated during Impaired Alveolarization of Mouse and Human Lungs

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