In addition to inhibiting cholesterol biosynthesis, statins also inhibit the formation of isoprenoid intermediates, which are required for the activation of the Rho/Rho kinase (ROCK) pathway. Increased ROCK activity has been implicated in causing endothelial dysfunction and atherosclerosis. However, it is not known whether statins, at doses used to lower cholesterol levels, inhibit ROCK activity in humans with atherosclerosis. Furthermore, it is not known whether lipophilic and hydrophilic statins differ in their ability to inhibit ROCK activity. Accordingly, we enrolled 30 male subjects with stable atherosclerosis (low-density lipoprotein (LDL) ≥ 100 mg/dL) in a randomized, double-blind study comparing equivalent LDL-lowering doses of a hydrophilic statin (rosuvastatin 10 mg daily) to a lipophilic statin (atorvastatin 40 mg daily) for 28 days. We assessed the change in lipids, ROCK activity, and flow-mediated dilation of the brachial artery (FMD) before, and after statin therapy. Both treatment groups exhibited comparable 30-32% and 42-45% reductions in total and LDL cholesterol, respectively. Only atorvastatin reduced triglycerides and neither statin altered high-density lipoprotein cholesterol. While both statins inhibited ROCK activity (p<0.0001), the extent of inhibition was greater with rosuvastatin (18±2% vs. 8±2%, p=0.0006). Statins also improved FMD from 7.4±0.6 to 9.3±0.4 (p=0.003) with rosuvastatin being slightly better than atorvastatin. The inhibition of ROCK activity by statins did not correlate with reductions in LDL (p=0.57), but was associated with improvement in FMD. These findings provide direct clinical evidence that statins, at clinically relevant doses, could differentially inhibit ROCK activity and improve endothelial function by cholesterol-independent mechanism. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Rho is a member of a large family of small GTPases, and together with its downstream target, ROCK, regulate organization of cytoskeletal proteins and other vital cellular functions. 1 Abnormal activation of ROCK has been observed in animal models of vascular injury. 2 In addition to inhibiting cholesterol synthesis, statins prevent the formation of isoprenoid intermediates such as geranylgeranyl pyrophosphate. 3 These isoprenoid intermediates are lipid attachments that are required for the membrane translocation and GTP-binding activity of Rho. Indeed, the inhibition of Rho/ROCK pathway has been implicated as a potential mechanism for some of the beneficial effects of statin therapy. Direct inhibition of Rho/ROCK pathway in cell cultu...