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

• Published in: Journal of thrombosis and haemostasis Vol. 5; no. 6; pp. 1170 - 1178
• Main Authors: PIGNATELLI, P., SANGUIGNI, V., LENTI, L., LOFFREDO, L., CARNEVALE, R., SORGE, R., VIOLI, F.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.06.2007
• Subjects: Atorvastatin Calcium; Autoantibodies - blood; Blood Platelets - drug effects; Blood Platelets - immunology; Blood Platelets - metabolism; Case-Control Studies; CD40 Ligand - blood; CD40L; Enzyme Inhibitors - therapeutic use; Female; Heptanoic Acids - therapeutic use; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Hypercholesterolemia - blood; Hypercholesterolemia - drug therapy; Hypercholesterolemia - immunology; In Vitro Techniques; Male; Middle Aged; NADPH Oxidases - antagonists & inhibitors; NADPH Oxidases - blood; Oxidative Stress; Platelet Glycoprotein GPIIb-IIIa Complex - immunology; Pyrroles - therapeutic use; statin; superoxide anion; Superoxides - blood; Up-Regulation
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/j.1538-7836.2007.02533.x

Objectives: We speculated that in patients with hypercholesterolemia CD40L overexpression could depend on low‐density lipoprotein (LDL)‐induced enhanced intraplatelet formation of O2·− and statin could reduce platelet CD40L via interference with platelet O2·− 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 O2·− 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. O2·− 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 O2·− (P < 0.001). Platelet CD40L was significantly correlated with O2·− (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 O2·− (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 O2·− 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.