Interaction between the Elastin Peptide VGVAPG and Human Elastin Binding Protein

Blanchevoye, Charlotte; Floquet, Nicolas; Scandolera, Amandine; Baud, Stéphanie; Maurice, Pascal; Bocquet, Olivier; Blaise, Sébastien; Ghoneim, Christelle; Cantarelli, Benoît; Delacoux, Frédéric; Dauchez, Manuel; Efremov, Roman G.; Martiny, Laurent; Duca, Laurent; Debelle, Laurent

doi:10.1074/jbc.m112.419929

Cited by 53 publications

(56 citation statements)

References 37 publications

(48 reference statements)

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“…31 This polarization of lymphocytes appears to be mediated through a receptor for specific EDPs, since it can be blocked by neutralization of the elastin receptor or with lactose, which causes shedding of the receptor from the cell membrane. 5 Similar treatment inhibited monocyte migration when monocytes were exposed to human AAA tissue extract. 13 A previous study has suggested that EDPs may have an anti-inflammatory effect on macrophages under specific conditions.…”

Section: Discussionmentioning

confidence: 99%

“…4 Elastin proteolysis releases elastin-derived peptides (EDPs), including peptides with the xGxxPG motif, a commonly repeated sequence in elastin. 5 Of those EDPs released by elastin degradation, the VGVAPG repeat sequence in the human tropoelastin molecule has been shown to have the highest affinity for elastin-binding protein. 5–8 EDPs are upregulated in the serum of patients with AAA, and an increase in their level is predictive of AAA expansion.…”

Section: Introductionmentioning

confidence: 99%

“…5 Of those EDPs released by elastin degradation, the VGVAPG repeat sequence in the human tropoelastin molecule has been shown to have the highest affinity for elastin-binding protein. 5–8 EDPs are upregulated in the serum of patients with AAA, and an increase in their level is predictive of AAA expansion. 9–11 Previous reports have demonstrated that EDPs recruit inflammatory cells to sites of ECM damage and neutralizing their effect with BA4, a monoclonal antibody that binds to VGVAPG and other xGxxPG motifs, prevents elastin damage.…”

Section: Introductionmentioning

confidence: 99%

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Elastin-Derived Peptides Promote Abdominal Aortic Aneurysm Formation by Modulating M1/M2 Macrophage Polarization

Dale

Xiong

Carson

et al. 2016

The Journal of Immunology

104

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Abdominal aortic aneurysm (AAA) is a dynamic vascular disease characterized by inflammatory cell invasion and extracellular matrix (ECM) degradation. Damage to elastin in the ECM results in release of elastin-derived peptides (EDPs), which are chemotactic for inflammatory cells such as monocytes. Their effect on macrophage polarization is less well known. Pro-inflammatory M1 macrophages initially are recruited to sites of injury but, if their effects are prolonged, they can lead to chronic inflammation that prevents normal tissue repair. Conversely, anti-inflammatory M2 macrophages reduce inflammation and aid in wound healing. Thus, a proper M1/M2 ratio is vital for tissue homeostasis. AAA tissue reveals a high M1/M2 ratio where pro-inflammatory cells and their associated markers dominate. In the present study, in vitro treatment of bone marrow-derived macrophages with EDPs induced M1 macrophage polarization. By using C57Bl/6 mice, antibody-mediated neutralization of EDPs reduced aortic dilation, matrix metalloproteinase activity, and pro-inflammatory cytokine expression at early and late time points after aneurysm induction. Furthermore, direct manipulation of the M1/M2 balance altered aortic dilation. Injection of M2 polarized macrophages reduced aortic dilation after aneurysm induction. EDPs promoted a pro-inflammatory environment in aortic tissue by inducing M1 polarization and neutralization of EDPs attenuated aortic dilation. The M1/M2 imbalance is vital to aneurysm formation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Elastin-Derived Peptides Promote Abdominal Aortic Aneurysm Formation by Modulating M1/M2 Macrophage Polarization

Dale

Xiong

Carson

et al. 2016

The Journal of Immunology

104

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“…The elastin fragments XGXXPG (where X is a generic hydrophobic residue) lead to expression and activation of MMP-1 and MMP-3 in human fibroblasts, suggesting the consensus sequence found in VGVAPG is important for binding to the elastin binding protein (EBP) receptor 36; 37 . This MMP activation in turn worsens local connective tissue damage.…”

Section: Elastin Peptides Are Generation By Mmpsmentioning

confidence: 99%

MMP generated matrikines

2015

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Matrikines originate from the fragmentation of extracellular matrix proteins and regulate cellular activities by interacting with specific receptors. Matrikines are implicated in inflammation, immune responses, organ development, wound repair, angiogenesis, atherosclerosis, tumor progression and metastasis due to their ability to alter cellular migration, chemotaxis, and mitogenesis. Matrix metalloproteinases (MMPs) degrade extracellular matrix components under normal circumstances and in disease processes. Of the 20 MMPs identified, MMP-1, MMP-2, MMP-8, MMP-9, and MMP-12 have been implicated in regulating the matrikines val-gly-val-ala-pro-gly (elastin peptide) and proline-glycine-proline (PGP). Elastin peptide fragments are generated from elastolytic enzymes and have implications in atherosclerosis, neovascularization, chronic obstructive pulmonary disease, skin disease, as well as tumor invasion and spread. PGP is produced through a multistep pathway that liberates the tripeptide fragment from extracellular collagen. PGP is best described for its role in neutrophil chemotaxis and is implicated in the pathogenesis of corneal ulcers and in chronic lung conditions. In chronic cigarette smoke related lung disease, the PGP pathway can become a self-propagating cycle of inflammation through cigarette-smoke mediated inhibition of leukotriene A4 hydrolase, the enzyme responsible for degrading PGP and halting acute inflammation. This review highlights the roles of MMPs in generating these important matrikines.

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“…Because of the complex nature of kE, we systematically used the VGVAPG peptide versus a scrambled peptide (VVGPGA) in the following experiments to specifically focus on the ERC in these processes because this peptide is known to bind specifically to the EBP subunit of this receptor. 29,30 Indeed, ≈29 different peptides were identified in kE mixtures by mass spectrometry analysis with one third containing the bioactive GxxPG motif (not shown). 14 In contrast, the scrambled VVGPGA is unable to adopt the type VIII β-turn conformation because of the lack of GxxPG motif.…”

Section: Discussionmentioning

confidence: 99%

Elastin-Derived Peptides Are New Regulators of Thrombosis

Kawecki

Hézard

Bocquet

et al. 2014

ATVB

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Objective-Elastin is the major structural extracellular matrix component of the arterial wall that provides the elastic recoil properties and resilience essential for proper vascular function. Elastin-derived peptides (EDP) originating from elastin fragmentation during vascular remodeling have been shown to play an important role in cell physiology and development of cardiovascular diseases. However, their involvement in thrombosis has been unexplored to date. In this study, we investigated the effects of EDP on (1) platelet aggregation and related signaling and (2) thrombus formation. We also characterized the mechanism by which EDP regulate thrombosis. Approach and Results-We show that EDP, derived from organo-alkaline hydrolysate of bovine insoluble elastin (kappaelastin), decrease human platelet aggregation in whole blood induced by weak and strong agonists, such as ADP, epinephrine, arachidonic acid, collagen, TRAP, and U46619. In a mouse whole blood perfusion assay over a collagen matrix, kappa-elastin and VGVAPG, the canonical peptide recognizing the elastin receptor complex, significantly decrease thrombus formation under arterial shear conditions. We confirmed these results in vivo by demonstrating that both kappa-elastin and VGVAPG significantly prolonged the time for complete arteriole occlusion in a mouse model of thrombosis and increased tail bleeding times. Finally, we demonstrate that the regulatory role of EDP on thrombosis relies on platelets that express a functional elastin receptor complex and on the ability of EDP to disrupt plasma von Willebrand factor interaction with collagen. Conclusions-These

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Interaction between the Elastin Peptide VGVAPG and Human Elastin Binding Protein

Cited by 53 publications

References 37 publications

Elastin-Derived Peptides Promote Abdominal Aortic Aneurysm Formation by Modulating M1/M2 Macrophage Polarization

Elastin-Derived Peptides Promote Abdominal Aortic Aneurysm Formation by Modulating M1/M2 Macrophage Polarization

MMP generated matrikines

Elastin-Derived Peptides Are New Regulators of Thrombosis

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