Abstract 5457: Intensive Treatment with Atorvastatin Inhibits Rho Kinase Activity in Patients with Atherosclerosis
Objectives: In addition to inhibiting cholesterol synthesis, statins (HMG-CoA reductase inhibitors) decrease the formation of isoprenoid intermediates required for the activation of key signaling pathways, including Rho/Rho kinase. In experimental settings, statins inhibit Rho/Rho kinase and thus exert pleiotropic effects by reversing vascular dysfunctions characteristic of atherosclerosis, independent of cholesterol reduction. Using our validated assay of Rho kinase activity in circulating leukocytes, we investigated whether atorvastatin inhibits the Rho/Rho kinase pathway in humans with atherosclerosis in clinically utilized doses.
Methods: We studied 35 patients with stable atherosclerosis in a randomized, double-blind study comparing treatment with high-dose (80 mg/d) or low-dose (10 mg/d) atorvastatin to placebo for 28 days. Blood samples for fasting lipids and leukocyte Rho kinase activity were assayed at days 0, 7, 14, and 28 after randomization and change over time with the 2 statin treatments relative to placebo was examined using repeated measures longitudinal regression analysis.
Results: While lipid levels decreased significantly with both high- and low-dose atorvastatin (p<0.0001), only atorvastatin 80 mg/d reduced Rho kinase activity (49 ± 20% inhibition) at 28 days compared to placebo (p=0.002). This decline was significant within 2 weeks of treatment. The inhibition of Rho kinase by atorvastatin (80 mg/d) remained significant even after controlling for changes in low-density lipoprotein (LDL) cholesterol and triglycerides (p=0.01). There was no statistical correlation between change in LDL cholesterol or change in triglycerides and change in Rho kinase activity.
Conclusions: These first-in-man findings demonstrate that high-dose atorvastatin rapidly inhibits the pro-atherogenic Rho/Rho kinase pathway. This inhibition is, in part, independent of cholesterol reduction. As Rho/Rho kinase activation leads to vascular dysfunctions (endothelial dysfunction, inflammation, proliferation), inhibition of this pathway may account for some of the ‘pleiotropic’ benefits of atorvastatin in humans. Rho/Rho kinase may provide a useful therapeutic target in patients with atherosclerosis.
This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).