Fluvastatin reduces soluble P-selectin and ICAM-1 levels in hypercholesterolemic patients: Role of nitric oxide

Background: Lipid-lowering therapy with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors reduces the incidence of atherosclerosis-r elated cardiovascular events. Adhesion molecules, regulating interactions b etween vascular and circulating cells, may play a central role in the patho genesis of atherosclerosis and related complications. In the present report we examined the impact of the HMG-CoA reductase inhibitor fluvastatin on p lasma levels of P-selectin and ICAM-1. Methods: Plasma levels of P-selectin and ICAM-1 were determined using an en zyme immunoassay in 26 patients with type IIa hypercholesterolemia randomiz ed to treatment with either fluvastatin (80 mg/d) or placebo in a double bl ind fashion for 12 weeks. Results: Fluvastatin administration reduced either P-selectin (118+/-63 vs 81+/-36 ng/mL [-31%], P=0.0015) or ICAM-1 (264+/-75 vs 228+/-68 ng/mL [-13. 7%], P=0.0033) levels. Fluva-statin also lowered urinary 11-dehydro-TXB2 (1 396+/-536 vs 1009+/-378 pg/mg creatinine [-27%], P=0.,0015) and von Willebr and Factor levels (1456+/-716 vs 1203+/-527 U/L [-17.4%], P=0.0275), and a direct correlation was observed between P-selectin and 11-dehydro-TXB2 leve ls (r=0.588, P=0.0033), Patients treated with fluvastatin displayed an incr ease in nitric oxide (NO) generation, evaluated with measurements of serum NO2-/NO3-, (4.7+/-1 vs 8.9+/-3.1 mu mol/L [98%], P=0.0046), Moreover, an in verse correlation was observed between NO2-/ NO3- and P-selectin (r=-0.320; P=0.0343), 11-dehydro-TXB2 (r= -0.511; P=0.0106), or LDL (r=-0.742; P=0.00 02) levels. Conclusions: These results may provide novel biochemical basis for the bene ficial clinical effects of HMG-CoA reductase inhibitors in hypercholesterol emia.