Hydroxy-methylglutaryl-coenzyme A reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance

Background-Hypercholesterolemia is causally associated with defects of endo thelial nitric oxide (NO)-dependent vasodilation. Increased uptake of chole sterol by endothelial cells (ECs) upregulates the abundance of the structur al protein caveolin-1 and impairs NO release through the stabilization of t he inhibitory heterocomplex between caveolin-1 and endothelial NO synthase (eNOS). Therefore, we examined whether the hydroxy-methylglutaryl-coenzyme A reductase inhibitor atorvastatin modulates caveolin abundance, eNOS activ ity, and NO release through a reduction in endogenous cholesterol levels. Methods and Results-ECs were incubated with increasing doses of atorvastati n in the absence or in the presence of human LDL cholesterol (LDL-Chol) fra ctions in the presence of antioxidants. Our results show that atorvastatin (10 nmol/L to 1 mu mol/L) reduced caveolin-1 abundance in the absence (-75% ) and in the presence (-20% to 70%) of LDL-Chol, This was paralleled by a d ecreased inhibitory interaction between caveolin-1 and eNOS and a restorati on and/or potentiation of the basal (+45%) and agonist-stimulated (+107%) e NOS activity. These effects were observed in the absence of changes in eNOS abundance and were reversed with mevalonate. In the presence of LDL-Chol, atorvastatin also promoted the agonist-induced association of eNOS and the chaperone Hsp90, resulting in the potentiation of eNOS activation. Conclusions-We provide biochemical and functional evidence that atorvastati n promotes NO production by decreasing caveolin-1 expression in ECs, regard less of the level of extracellular LDL-Chol. These findings highlight the t herapeutic potential of inhibiting cholesterol synthesis in peripheral cell s to correct NO-dependent endothelial dysfunction associated with hyperchol esterolemia and possibly other diseases.