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PCSK9 Regulates Nox2-Mediated Platelet Activation via CD36 Receptor in Patients with Atrial Fibrillation

Background: High levels of proprotein convertase subtilisin/kexin 9 (PCSK9) is predictive of cardiovascular events (CVEs) in atrial fibrillation (AF). We hypothesized that PCSK9 may directly induce platelet activation (PA). Methods: We measured platelet aggregation, recruitment, Thromboxane B2 (TxB2...

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Autores principales: Cammisotto, Vittoria, Pastori, Daniele, Nocella, Cristina, Bartimoccia, Simona, Castellani, Valentina, Marchese, Cinzia, Sili Scavalli, Antonio, Ettorre, Evaristo, Viceconte, Nicola, Violi, Francesco, Pignatelli, Pasquale, Carnevale, Roberto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222182/
https://www.ncbi.nlm.nih.gov/pubmed/32252393
http://dx.doi.org/10.3390/antiox9040296
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author Cammisotto, Vittoria
Pastori, Daniele
Nocella, Cristina
Bartimoccia, Simona
Castellani, Valentina
Marchese, Cinzia
Sili Scavalli, Antonio
Ettorre, Evaristo
Viceconte, Nicola
Violi, Francesco
Pignatelli, Pasquale
Carnevale, Roberto
author_facet Cammisotto, Vittoria
Pastori, Daniele
Nocella, Cristina
Bartimoccia, Simona
Castellani, Valentina
Marchese, Cinzia
Sili Scavalli, Antonio
Ettorre, Evaristo
Viceconte, Nicola
Violi, Francesco
Pignatelli, Pasquale
Carnevale, Roberto
author_sort Cammisotto, Vittoria
collection PubMed
description Background: High levels of proprotein convertase subtilisin/kexin 9 (PCSK9) is predictive of cardiovascular events (CVEs) in atrial fibrillation (AF). We hypothesized that PCSK9 may directly induce platelet activation (PA). Methods: We measured platelet aggregation, recruitment, Thromboxane B2 (TxB2) formation and soluble P-selectin levels as markers of PA and soluble Nox2-derived peptide (sNox2-dp), H(2)O(2), isoprostanes and oxidized Low-Density-Lipoprotein (oxLDL) to analyze oxidative stress (OS) in 88 patients having PCSK9 values < (n = 44) or > (n = 44) 1.2 ng/mL, balanced for age, sex and cardiovascular risk factors. Furthermore, we investigated if normal (n = 5) platelets incubated with PCSK9 (1.0–2.0 ng/mL) alone or with LDL (50 µg/mL) displayed changes of PA, OS and down-stream signaling. Results: PA and OS markers were significantly higher in patients with PCSK9 levels > 1.2 ng/mL compared to those with values < 1.2 ng/mL (p < 0.001). Levels of PCSK9 significantly correlated with markers of PA and OS. Platelets incubation with PCSK9 increased PA, OS and p38, p47 and Phospholipase A2 (PLA2) phosphorylation. These changes were amplified by adding LDL and blunted by CD36 or Nox2 inhibitors. Co-immunoprecipitation analysis revealed an immune complex of PCSK9 with CD36. Conclusions: We provide the first evidence that PCSK9, at concentration found in the circulation of AF patients, directly interacts with platelets via CD36 receptor and activating Nox2: this effect is amplified in presence of LDL.
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spelling pubmed-72221822020-05-28 PCSK9 Regulates Nox2-Mediated Platelet Activation via CD36 Receptor in Patients with Atrial Fibrillation Cammisotto, Vittoria Pastori, Daniele Nocella, Cristina Bartimoccia, Simona Castellani, Valentina Marchese, Cinzia Sili Scavalli, Antonio Ettorre, Evaristo Viceconte, Nicola Violi, Francesco Pignatelli, Pasquale Carnevale, Roberto Antioxidants (Basel) Article Background: High levels of proprotein convertase subtilisin/kexin 9 (PCSK9) is predictive of cardiovascular events (CVEs) in atrial fibrillation (AF). We hypothesized that PCSK9 may directly induce platelet activation (PA). Methods: We measured platelet aggregation, recruitment, Thromboxane B2 (TxB2) formation and soluble P-selectin levels as markers of PA and soluble Nox2-derived peptide (sNox2-dp), H(2)O(2), isoprostanes and oxidized Low-Density-Lipoprotein (oxLDL) to analyze oxidative stress (OS) in 88 patients having PCSK9 values < (n = 44) or > (n = 44) 1.2 ng/mL, balanced for age, sex and cardiovascular risk factors. Furthermore, we investigated if normal (n = 5) platelets incubated with PCSK9 (1.0–2.0 ng/mL) alone or with LDL (50 µg/mL) displayed changes of PA, OS and down-stream signaling. Results: PA and OS markers were significantly higher in patients with PCSK9 levels > 1.2 ng/mL compared to those with values < 1.2 ng/mL (p < 0.001). Levels of PCSK9 significantly correlated with markers of PA and OS. Platelets incubation with PCSK9 increased PA, OS and p38, p47 and Phospholipase A2 (PLA2) phosphorylation. These changes were amplified by adding LDL and blunted by CD36 or Nox2 inhibitors. Co-immunoprecipitation analysis revealed an immune complex of PCSK9 with CD36. Conclusions: We provide the first evidence that PCSK9, at concentration found in the circulation of AF patients, directly interacts with platelets via CD36 receptor and activating Nox2: this effect is amplified in presence of LDL. MDPI 2020-04-02 /pmc/articles/PMC7222182/ /pubmed/32252393 http://dx.doi.org/10.3390/antiox9040296 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cammisotto, Vittoria
Pastori, Daniele
Nocella, Cristina
Bartimoccia, Simona
Castellani, Valentina
Marchese, Cinzia
Sili Scavalli, Antonio
Ettorre, Evaristo
Viceconte, Nicola
Violi, Francesco
Pignatelli, Pasquale
Carnevale, Roberto
PCSK9 Regulates Nox2-Mediated Platelet Activation via CD36 Receptor in Patients with Atrial Fibrillation
title PCSK9 Regulates Nox2-Mediated Platelet Activation via CD36 Receptor in Patients with Atrial Fibrillation
title_full PCSK9 Regulates Nox2-Mediated Platelet Activation via CD36 Receptor in Patients with Atrial Fibrillation
title_fullStr PCSK9 Regulates Nox2-Mediated Platelet Activation via CD36 Receptor in Patients with Atrial Fibrillation
title_full_unstemmed PCSK9 Regulates Nox2-Mediated Platelet Activation via CD36 Receptor in Patients with Atrial Fibrillation
title_short PCSK9 Regulates Nox2-Mediated Platelet Activation via CD36 Receptor in Patients with Atrial Fibrillation
title_sort pcsk9 regulates nox2-mediated platelet activation via cd36 receptor in patients with atrial fibrillation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222182/
https://www.ncbi.nlm.nih.gov/pubmed/32252393
http://dx.doi.org/10.3390/antiox9040296
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