Objectives: We speculated that in patients with hypercholesterolemia CD40L overexpression could depend on low-density lipoprotein (LDL)-induced enhanced intraplatelet formation of O-2(.-) and statin could reduce platelet CD40L via interference with platelet O-2(.-) production. Background: CD40L is a protein with inflammatory and thrombotic properties. CD40L is upregulated in platelets from hypercholesterolemic (HC) patients but the underlying mechanism is unclear. Methods: Collagen-induced platelet CD40L and platelet O-2(.-) expression were investigated in 40 HC patients and 40 healthy subjects. HC patients were then randomized to either a diet (n = 20) (group A) or atorvastatin 10 mg day (n = 20) (group B); the above variables were measured at baseline and after 3 and 30 days of treatment. O-2(.-) and CD40L were also measured in vitro in LDL-treated platelets with or without nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor or atorvastatin added. Results: Compared with controls, HC patients showed higher values of platelet CD40L (P < 0.001) and O-2(.-) (P < 0.001). Platelet CD40L was significantly correlated with O-2(.-) (P < 0.001). The interventional trial showed no changes in group A and a significant and parallel decrease in platelet CD40L (P < 0.001) and O-2(.-) (P < 0.001) in group B. In vitro studies demonstrated that LDL-induced platelet CD40L and GP IIb/IIIa (PAC1 binding) activation via the NADPH oxidase pathway. CD40L upregulation was counteracted by atorvastatin in a dose-dependent fashion. Conclusions: This study suggests that in patients with hypercholesterolemia platelet CD40L is upregulated via NADPH oxidase-dependent O-2(.-) generation. Atorvastatin downregulated CD40L with an oxidative stress-mediated mechanism likely involving platelet NADPH oxidase, an effect that seemed to be independent of its cholesterol-lowering action.

Pignatelli, P., Sanguigni, V., Lenti, L., Loffredo, L., Carnevale, R., Sorge, R., et al. (2007). Oxidative stress-mediated platelet CD40 ligand upregulation in patients with hypercholesterolemia: effect of atorvastatin. JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 5(6), 1170-1178 [10.1111/j.1538-7836.2007.02533.x].

Oxidative stress-mediated platelet CD40 ligand upregulation in patients with hypercholesterolemia: effect of atorvastatin

SANGUIGNI, VALERIO;
2007

Abstract

Objectives: We speculated that in patients with hypercholesterolemia CD40L overexpression could depend on low-density lipoprotein (LDL)-induced enhanced intraplatelet formation of O-2(.-) and statin could reduce platelet CD40L via interference with platelet O-2(.-) production. Background: CD40L is a protein with inflammatory and thrombotic properties. CD40L is upregulated in platelets from hypercholesterolemic (HC) patients but the underlying mechanism is unclear. Methods: Collagen-induced platelet CD40L and platelet O-2(.-) expression were investigated in 40 HC patients and 40 healthy subjects. HC patients were then randomized to either a diet (n = 20) (group A) or atorvastatin 10 mg day (n = 20) (group B); the above variables were measured at baseline and after 3 and 30 days of treatment. O-2(.-) and CD40L were also measured in vitro in LDL-treated platelets with or without nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor or atorvastatin added. Results: Compared with controls, HC patients showed higher values of platelet CD40L (P < 0.001) and O-2(.-) (P < 0.001). Platelet CD40L was significantly correlated with O-2(.-) (P < 0.001). The interventional trial showed no changes in group A and a significant and parallel decrease in platelet CD40L (P < 0.001) and O-2(.-) (P < 0.001) in group B. In vitro studies demonstrated that LDL-induced platelet CD40L and GP IIb/IIIa (PAC1 binding) activation via the NADPH oxidase pathway. CD40L upregulation was counteracted by atorvastatin in a dose-dependent fashion. Conclusions: This study suggests that in patients with hypercholesterolemia platelet CD40L is upregulated via NADPH oxidase-dependent O-2(.-) generation. Atorvastatin downregulated CD40L with an oxidative stress-mediated mechanism likely involving platelet NADPH oxidase, an effect that seemed to be independent of its cholesterol-lowering action.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/09 - Medicina Interna
English
Con Impact Factor ISI
CD40L; Statin; Superoxide anion
apocynin; atorvastatin; CD40 ligand; cholesterol; collagen; fibrinogen receptor; glucose; high density lipoprotein cholesterol; low density lipoprotein; low density lipoprotein cholesterol; n(g) nitroarginine methyl ester; oxygen; reduced nicotinamide adenine dinucleotide phosphate oxidase; triacylglycerol; adult; antioxidant activity; article; cholesterol blood level; clinical article; clinical trial; concentration response; controlled clinical trial; controlled study; correlation analysis; diet therapy; drug mechanism; enzyme inhibition; female; glucose blood level; human; human cell; hypercholesterolemia; in vitro study; male; oxidative stress; priority journal; randomized controlled trial; signal transduction; thrombocyte metabolism; upregulation; Autoantibodies; Blood Platelets; Case-Control Studies; CD40 Ligand; Enzyme Inhibitors; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Middle Aged; NADPH Oxidase; Oxidative Stress; Platelet Glycoprotein GPIIb-IIIa Complex; Pyrroles; Superoxides; Up-Regulation
Pignatelli, P., Sanguigni, V., Lenti, L., Loffredo, L., Carnevale, R., Sorge, R., et al. (2007). Oxidative stress-mediated platelet CD40 ligand upregulation in patients with hypercholesterolemia: effect of atorvastatin. JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 5(6), 1170-1178 [10.1111/j.1538-7836.2007.02533.x].
Pignatelli, P; Sanguigni, V; Lenti, L; Loffredo, L; Carnevale, R; Sorge, R; Violi, F
Articolo su rivista
File in questo prodotto:
File Dimensione Formato  
JTH 07.pdf

accesso aperto

Descrizione: Articolo principale
Licenza: Creative commons
Dimensione 303.23 kB
Formato Adobe PDF
303.23 kB Adobe PDF Visualizza/Apri

Questo articolo è pubblicato sotto una Licenza Licenza Creative Commons Creative Commons

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/58168
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact