Abstract 1520: Oxidative Stress-Mediated Platelet CD40 Ligand Upregulation in Patients with Hypercholesterolemia. Effect of Atorvastatin
We investigated if in hypercholesterolemia overexpression of platelet CD40 ligand (CD40L), a surface-bound protein with inflammatory and pro-thrombotic effects, may depend on enhanced intraplatelet formation of superoxide anion(O2-) and therefore if atorvastatin could directly affects platelet CD40L expression via O2- production downregulation..
Methods: We compared 40 patients with polygenic hypercholesterolemia and 40 sex- and age-matched controls. Hypercholesterolemics were then randomized to either a diet (N=20) or atorvastatin 10 mg/day (N=20) for three days. Lipid profile, CD40 ligand platelet expression. and O2-production were measured at baseline and after 3 days of treatment. In vitro studies were also performed to investigate if LDL enhanced platelet CD40L expression and if atorvastatin, was able to down-regulate platelet CD40L expression.
Results: Compared with controls,patients with hypercholesterolemia had enhanced production of O2- (p<0.001) and higher platelet expression of CD40L (p<0.001). Platelet CD40L significantly correlated with platelet O2-(r=0.79) Both groups (diet and atorvastatin) did not show any changes in lipid profile after 3 days of treatment . In diet group (n=20), no changes in platelet CD40L expression and O2-production was observed. In atorvastatin group (n=20), a significant decrease in platelet CD40L (48.6 ± 15.2 vs 34.1 ± 7,3 AU, p < 0.001) and platelet O2- (4.2±0.5 vs 2.5±0.3 SI, p<0.01) was observed after three days. Before-after treatment changes between platelet CD40L and platelet O2-.( r=0.68), were significantly correlated. Incubation of LDL-treated platelets with apocynin ,an inhibitor of NADPH oxidase, significantly reduced platelet O2-formation(p < 0.001) and CD40L expression(p < 0.001); atorvastatin dose-dependently significant decreased platelet O2- ( p < 0.001)production and CD40L expression ( p < 0.005).
Conclusion: This study provides first evidence that in hypercholesterolemia, platelet CD40L overexpression may be mediated by enhanced platelet O2- production.Atorvastatin has a direct antioxidant effect, independently of its cholesterol-lowering effect, that accounts for reduced platelet production of O2- and in turn platelet CD40L downregulation,