Abstract 10321: Oral Atorvastatin Treatment Improves NO Bioavailability and Vascular Redox State in the Human Arterial Wall, via a Tetrahydrobiopterin-Mediated Improvement of eNOS Coupling
Background: The exact mechanisms by which statins affect endothelial nitric oxide synthase (eNOS) biology in human atherosclerosis are unclear. We hypothesized that statin treatment improves nitric oxide (NO) bioavailability reduces arterial superoxide (O2-) generation in human arterial wall by modifying eNOS coupling via a tetrahydrobiopterin (BH4)-mediated mechanism.
Methods: In Study 1, in 492 patients undergoing CABG, endothelial function was evaluated by flow-mediated dilation in the brachial artery (FMD) and by ex-vivo vasomotor studies of saphenous veins (SV), while vascular O2- was determined in mammary arteries (IMA) by lucigenin chemiluminescence. In Study 2, 42 patients undergoing CABG were randomized to receive atorvastatin 40mg/day or placebo for 3 days preoperatively. FMD was determined at baseline and before CABG, while IMAs were used to measure arterial O2- and vascular BH4.
Results: In Study 1, statin treatment was an independent predictor of FMD (β(SE)=1.3(0.5), P=0.01)) and arterial O2- (β(SE)=-0.4(0.08), P=0.0001). Patients receiving statins had better SV vasorelaxations to acetylcholine (A) and less arterial O2-(B). In Study 2, atorvastatin improved FMD (C), reduced arterial O2- (D) and improved LNAME-delta(O2-)(E), suggesting improved eNOS coupling. This effect was due to improved BH4 bioavailability in these vessels (F). All effects were independent of LDL lowering.
Conclusions: This study demonstrates for the first time that statin treatment is directly associated with reduced arterial O2- and improved NO bioavailability in the human arterial wall, through a BH4-mediated improvement of eNOS coupling. These findings provide an additional mechanism by which statins exert their beneficial vascular effects, and identify eNOS coupling and vascular BH4 availability as rational therapeutic targets in human atherosclerosis.
- © 2011 by American Heart Association, Inc.