Abstract 10311: Rapid Effects of Atorvastatin on Tetrahydrobiopterin-Mediated eNOS Coupling in Human Arteries, is Mediated by Stimulation of Vascular GTP-Cyclohydrolase
Background: Statins improve survival of patients with atherosclerosis, but their direct effects on human arterial wall are unclear. We examined the effect of atorvastatin on the mechanisms regulating endothelial nitric oxide synthase (eNOS) coupling in human arteries.
Methods: Segments of internal mammary arteries (IMA) obtained from 26 patients undergoing CABG, were exposed to atorvastatin 0, 5 μ mol/L for 6 hours ex vivo. Then vascular O2- was measured in by lucigenin chemiluminescence in the presence of eNOS inhibitor LNAME, and/or mevalonate (200μ mol/L). The effect of atorvastatin on vascular tetrahydrobiopterin (BH4) and the rate-limiting enzyme of its synthesis, GTP- cyclohydrolase I (GTPCH I), were determined. The direct effect of atorvastatin on Rac1 activation was also determined.
Results: Atorvastatin reduced Rac1 activation, reduced vascular (O2-) and reversed LNAME-inhibitable O2- (A), suggesting an improvement of eNOS coupling. These effects were prevented by mevalonate (A). Atorvastatin induced a significant increase of vascular BH4 and total biopterins(B) by increasing GTPCHI enzymatic activity, an effect that was reversed by DAHP (B). Atorvastatin also significantly increased GTPCH1 mRNA (C).
Conclusions: This study demonstrates for the first time in humans that atorvastatin exerts a rapid, direct effect on GTPCHI expression in human arteries, increasing BH4 bioavailability and eNOS coupling. This results into a striking improvement of vascular redox state, documenting an additional pleiotropic effect of statins on the arterial wall of patients with advanced atherosclerosis.
- © 2011 by American Heart Association, Inc.