title: Oxidative stress-mediated platelet CD40 ligand upregulation in patients with hypercholesterolemia: effect of atorvastatin.
abstract: OBJECTIVE
  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.
authors: Department of Experimental Medicine and Pathology, University of Rome La Sapienza, Rome, Italy.
authors: P
authors: P
authors: Pignatelli
authors: V
authors: V
authors: Sanguigni
authors: L
authors: L
authors: Lenti
authors: L
authors: L
authors: Loffredo
authors: R
authors: R
authors: Carnevale
authors: R
authors: R
authors: Sorge
authors: F
authors: F
authors: Violi
mesh_terms: D000069059:Atorvastatin; D001323:Autoantibodies / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D023201:CD40 Ligand / Q000097:blood*; D016022:Case-Control Studies; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood* / Q000188:drug therapy* / Q000276:immunology; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000097:blood; D018384:Oxidative Stress; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000276:immunology; D011758:Pyrroles / Q000627:therapeutic use*; D013481:Superoxides / Q000097:blood; D015854:Up-Regulation
chemical_list: D001323:Autoantibodies; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011758:Pyrroles; D013481:Superoxides; D023201:CD40 Ligand; D000069059:Atorvastatin; D019255:NADPH Oxidases