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), H2O2, 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.

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. - In: ANTIOXIDANTS. - ISSN 2076-3921. - 9:4(2020). [10.3390/antiox9040296]

PCSK9 regulates Nox2-mediated platelet activation via CD36 receptor in patients with atrial fibrillation

Vittoria Cammisotto
Primo
;
Daniele Pastori;Cristina Nocella;Simona Bartimoccia;Valentina Castellani;Cinzia Marchese;Antonio Sili Scavalli;Evaristo Ettorre;Nicola Viceconte;Francesco Violi;Pasquale Pignatelli
Penultimo
;
Roberto Carnevale
Ultimo
2020

Abstract

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), H2O2, 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.
2020
CD36; PCSK9; ROS; oxidative stress; platelets
01 Pubblicazione su rivista::01a Articolo in rivista
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. - In: ANTIOXIDANTS. - ISSN 2076-3921. - 9:4(2020). [10.3390/antiox9040296]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1385761
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