The effects of HMG-CoA reductase inhibitors on endothelial function

Vascular endothelial dysfunction is a complex phenomenon that is caused by an imbalance of vasodilator and vasoconstrictor factors that regulate the equilibrium-maintaining vascular tone. In the early phase of hypercholesterolemia, endothelial dysfunction precedes vascular wall lesions. One of the earliest recognizable benefits of treatment with HMG-CoA reductase inhibitors (statins) is the normalization of endothelium-dependent relaxation in hypercholesterolemia; this effect occurs before significant lowering of serum cholesterol levels. Recent insights into cellular mechanisms indicate that statins promote vasorelaxation by upregulating the expression of endothelial nitric oxide (NO) synthase, activating the phosphatidylinositide 3-kinase/Akt pathway, inhibiting superoxide anion generation and endothelin synthesis, and by anti-inflammatory effects. These effects appear to be linked to the inhibition of geranylgeranylation of small G proteins such as Rho and Rac GTPases. In this regard, statins preserve endothelial function through the improvement of NO bioavailability and the reduction of oxidative stress, thereby shifting the balance from vasoconstriction to vasodilation. This review highlights the various mechanisms underlying the vasculoprotective effects of statins, independent of their effects on cholesterol lowering.