3-hydroxy-3-methylglutaryl-coenzyme-A-reductase inhibitors (statins) are the most effective drugs for lowering serum cholesterol. However, acute discontinuation of statins impair vascular function and increase adverse cardiovascular events. Because of its clinical relevance, the mechanisms underlying the vascular dysfunction associated with statin withdrawal are under active investigation. Vascular protective mechanisms, such as nitric oxide production and endothelial-dependent vasodilation, are impaired after acute statin discontinuation. We have also shown that angiotensin II (AII)-signaling, and the mRNA and protein levels for AT1 receptors (AII primary receptor) are increased after statin withdrawal. Since AII vasoconstrictor, inflammatory and growth promoting effects on the vasculature are well known, our findings suggest that AII may participate in vascular dysfunction following statin discontinuation. Current evidence indicates that by inhibiting mevalonate formation, statins decrease intracellular levels of isoprenoid intermediates, reducing the levels of prenylated membrane-bound (active) rhoA small GTPase. The latter, is known to reduce expression and levels of AT1 receptors. It is thus feasible that the opposite effect may determine the upregulation of AT1-receptors and AIIsignaling observed after statin withdrawal. Consequently, in this proposal, we would like to study the intracellular mechanisms determining the upregulation of AT1 receptors and AIIsignaling observed after statin withdrawal. Experiments will be conducted in vascular smooth muscle cells (VSMC) in the presence of selective inhibitors and stimulators of farnesylation and of geranylgeranylation. Completion of these experiments will allow us to determine the relative role of farnesylation and geranylgeranylation in the upregulation of AII receptors and signaling after statin withdrawal, and to test our hypothesis that the upregulation of AII is due to increased isoprenylation of small GTPases. In summary, the relevance of this research project is to further elucidate the vascular mechanisms by which statins withdrawal may impair cardiovascular functions, and to investigate the role of the cholesterol biosynthetic pathway on vascular function.