Secreted phospholipases A2 in hereditary angioedema with C1-inhibitor deficiency

Stefania Loffredo, Anne Lise Ferrara, Maria Bova, Francesco Borriello, Chiara Suffritti, Nóra Veszeli, Angelica Petraroli, Maria Rosaria Galdiero, Gilda Varricchi, Francescopaolo Granata, Andrea Zanichelli, H. Farkas, Marco Cicardi, Gérard Lambeau, Gianni Marone

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: Hereditary angioedema (HAE) caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein (C1-INH-HAE) is a disabling, potentially fatal condition characterized by recurrent episodes of swelling. We have recently found that patients with C1-INH-HAE have increased plasma levels of vascular endothelial growth factors and angiopoietins (Angs), which have been associated with vascular permeability in several diseases. Among these and other factors, blood endothelial cells and vascular permeability can be modulated by extracellular or secreted phospholipases A2 (sPLA2s). Objective: We sought to investigate the enzymatic activity and biological functions of sPLA2 in patients with C1-INH-HAE. Methods: sPLA2s enzymatic activity was evaluated in the plasma from 109 adult patients with C1-INH-HAE and 68 healthy donors in symptom-free period and attacks. Plasma level of group IIA sPLA2 (hGIIA) protein was measured in selected samples. The effect of C1-INH-HAE plasma on endothelial permeability was examined in vitro using a vascular permeability assay. The role of hGIIA was determined using highly specific sPLA2 indole inhibitors. The effect of recombinant hGIIA on C1-INH activity was examined in vitro by functional assay. Results: Plasma sPLA2 activity and hGIIA levels are increased in symptom-free C1-INH-HAE patients compared with controls. sPLA2 activity negatively correlates with C1-INH protein level and function. C1-INH-HAE plasma increases endothelial permeability in vitro, and this effect is partially reverted by a specific hGIIA enzymatic inhibitor. Finally, recombinant hGIIA inhibits C1-INH activity in vitro. Conclusion: sPLA2 enzymatic activity (likely attributable to hGIIA), which is increased in C1-INH-HAE patients, can promote vascular permeability and impairs C1-INH activity. Our results may pave the way for investigating the functions of sPLA2s (in particular, hGIIA) in the pathophysiology of C1-INH-HAE and may inform the development of new therapeutic targets.

Original languageEnglish
Article number1721
JournalFrontiers in Immunology
Volume9
Issue numberJUL
DOIs
Publication statusPublished - Jul 23 2018

Fingerprint

Secretory Phospholipase A2
Hereditary Angioedemas
Capillary Permeability
Complement C1 Inhibitor Protein
Permeability
Vascular Endothelial Growth Factors
Angiopoietins
Blood Cells
Endothelial Cells
Tissue Donors

Keywords

  • Angiogenesis
  • Angiopoietins
  • C1 inhibitor deficiency
  • Hereditary angioedema
  • Phospholipase A
  • Vascular endothelial growth factor
  • Vascular permeability

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Loffredo, S., Ferrara, A. L., Bova, M., Borriello, F., Suffritti, C., Veszeli, N., ... Marone, G. (2018). Secreted phospholipases A2 in hereditary angioedema with C1-inhibitor deficiency. Frontiers in Immunology, 9(JUL), [1721]. https://doi.org/10.3389/fimmu.2018.01721

Secreted phospholipases A2 in hereditary angioedema with C1-inhibitor deficiency. / Loffredo, Stefania; Ferrara, Anne Lise; Bova, Maria; Borriello, Francesco; Suffritti, Chiara; Veszeli, Nóra; Petraroli, Angelica; Galdiero, Maria Rosaria; Varricchi, Gilda; Granata, Francescopaolo; Zanichelli, Andrea; Farkas, H.; Cicardi, Marco; Lambeau, Gérard; Marone, Gianni.

In: Frontiers in Immunology, Vol. 9, No. JUL, 1721, 23.07.2018.

Research output: Contribution to journalArticle

Loffredo, S, Ferrara, AL, Bova, M, Borriello, F, Suffritti, C, Veszeli, N, Petraroli, A, Galdiero, MR, Varricchi, G, Granata, F, Zanichelli, A, Farkas, H, Cicardi, M, Lambeau, G & Marone, G 2018, 'Secreted phospholipases A2 in hereditary angioedema with C1-inhibitor deficiency', Frontiers in Immunology, vol. 9, no. JUL, 1721. https://doi.org/10.3389/fimmu.2018.01721
Loffredo S, Ferrara AL, Bova M, Borriello F, Suffritti C, Veszeli N et al. Secreted phospholipases A2 in hereditary angioedema with C1-inhibitor deficiency. Frontiers in Immunology. 2018 Jul 23;9(JUL). 1721. https://doi.org/10.3389/fimmu.2018.01721
Loffredo, Stefania ; Ferrara, Anne Lise ; Bova, Maria ; Borriello, Francesco ; Suffritti, Chiara ; Veszeli, Nóra ; Petraroli, Angelica ; Galdiero, Maria Rosaria ; Varricchi, Gilda ; Granata, Francescopaolo ; Zanichelli, Andrea ; Farkas, H. ; Cicardi, Marco ; Lambeau, Gérard ; Marone, Gianni. / Secreted phospholipases A2 in hereditary angioedema with C1-inhibitor deficiency. In: Frontiers in Immunology. 2018 ; Vol. 9, No. JUL.
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AU - Loffredo, Stefania

AU - Ferrara, Anne Lise

AU - Bova, Maria

AU - Borriello, Francesco

AU - Suffritti, Chiara

AU - Veszeli, Nóra

AU - Petraroli, Angelica

AU - Galdiero, Maria Rosaria

AU - Varricchi, Gilda

AU - Granata, Francescopaolo

AU - Zanichelli, Andrea

AU - Farkas, H.

AU - Cicardi, Marco

AU - Lambeau, Gérard

AU - Marone, Gianni

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N2 - Background: Hereditary angioedema (HAE) caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein (C1-INH-HAE) is a disabling, potentially fatal condition characterized by recurrent episodes of swelling. We have recently found that patients with C1-INH-HAE have increased plasma levels of vascular endothelial growth factors and angiopoietins (Angs), which have been associated with vascular permeability in several diseases. Among these and other factors, blood endothelial cells and vascular permeability can be modulated by extracellular or secreted phospholipases A2 (sPLA2s). Objective: We sought to investigate the enzymatic activity and biological functions of sPLA2 in patients with C1-INH-HAE. Methods: sPLA2s enzymatic activity was evaluated in the plasma from 109 adult patients with C1-INH-HAE and 68 healthy donors in symptom-free period and attacks. Plasma level of group IIA sPLA2 (hGIIA) protein was measured in selected samples. The effect of C1-INH-HAE plasma on endothelial permeability was examined in vitro using a vascular permeability assay. The role of hGIIA was determined using highly specific sPLA2 indole inhibitors. The effect of recombinant hGIIA on C1-INH activity was examined in vitro by functional assay. Results: Plasma sPLA2 activity and hGIIA levels are increased in symptom-free C1-INH-HAE patients compared with controls. sPLA2 activity negatively correlates with C1-INH protein level and function. C1-INH-HAE plasma increases endothelial permeability in vitro, and this effect is partially reverted by a specific hGIIA enzymatic inhibitor. Finally, recombinant hGIIA inhibits C1-INH activity in vitro. Conclusion: sPLA2 enzymatic activity (likely attributable to hGIIA), which is increased in C1-INH-HAE patients, can promote vascular permeability and impairs C1-INH activity. Our results may pave the way for investigating the functions of sPLA2s (in particular, hGIIA) in the pathophysiology of C1-INH-HAE and may inform the development of new therapeutic targets.

AB - Background: Hereditary angioedema (HAE) caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein (C1-INH-HAE) is a disabling, potentially fatal condition characterized by recurrent episodes of swelling. We have recently found that patients with C1-INH-HAE have increased plasma levels of vascular endothelial growth factors and angiopoietins (Angs), which have been associated with vascular permeability in several diseases. Among these and other factors, blood endothelial cells and vascular permeability can be modulated by extracellular or secreted phospholipases A2 (sPLA2s). Objective: We sought to investigate the enzymatic activity and biological functions of sPLA2 in patients with C1-INH-HAE. Methods: sPLA2s enzymatic activity was evaluated in the plasma from 109 adult patients with C1-INH-HAE and 68 healthy donors in symptom-free period and attacks. Plasma level of group IIA sPLA2 (hGIIA) protein was measured in selected samples. The effect of C1-INH-HAE plasma on endothelial permeability was examined in vitro using a vascular permeability assay. The role of hGIIA was determined using highly specific sPLA2 indole inhibitors. The effect of recombinant hGIIA on C1-INH activity was examined in vitro by functional assay. Results: Plasma sPLA2 activity and hGIIA levels are increased in symptom-free C1-INH-HAE patients compared with controls. sPLA2 activity negatively correlates with C1-INH protein level and function. C1-INH-HAE plasma increases endothelial permeability in vitro, and this effect is partially reverted by a specific hGIIA enzymatic inhibitor. Finally, recombinant hGIIA inhibits C1-INH activity in vitro. Conclusion: sPLA2 enzymatic activity (likely attributable to hGIIA), which is increased in C1-INH-HAE patients, can promote vascular permeability and impairs C1-INH activity. Our results may pave the way for investigating the functions of sPLA2s (in particular, hGIIA) in the pathophysiology of C1-INH-HAE and may inform the development of new therapeutic targets.

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