Inhibition of geranylgeranyltransferase I decreases generation of vascular reactive oxygen species and increases vascular nitric oxide production 1

Abstract

Vascular injury with endothelial dysfunction results in an imbalance between the production of vasoprotective molecules such as nitric oxide (NO) and deleterious reactive oxygen species (ROS). The purpose of this work was to test the hypothesis that inhibition of geranylgeranyltransferase I (GG Tase I) reduces vascular injury by increasing vascular NO production while decreasing ROS generation. GGTI-298 decreased the formation of intimal hyperplasia at 14 days following balloon injury. GGTI-298 (10 microm) inhibited activation of RhoA and Rac1 as well as inhibited SMC proliferation. GGTI increased SMC-inducible NO synthase (iNOS) levels and NO production in vitro. Additionally, the activation of NAD(P)H oxidase subunits was decreased by GGTI in vitro. This correlated with a decrease in TNF-alpha- or angiotensin-II-induced ROS production assayed by DCF fluorescence. In vivo, GGTI treatment increased endothelial NOS (eNOS) expression in uninjured arteries and iNOS expression in balloon-injured arteries. Furthermore, GGTI treatment attenuated balloon-injury-induced superoxide generation assayed by MCLA luminescence. GGTI decreases the production of ROS and increases the production of NO both in vitro and in vivo. These effects may be mediated via the inhibition of activation of the small GTPases Rac1 and RhoA. Pharmacological inhibition of GGTase I may prove to be a useful clinical adjunct in the treatment of cardiovascular diseases.