title: Rapid, direct effects of statin treatment on arterial redox state and nitric oxide bioavailability in human atherosclerosis via tetrahydrobiopterin-mediated endothelial nitric oxide synthase coupling.
abstract: BACKGROUND
  Treatment with statins improves clinical outcome, but the exact mechanisms of pleiotropic statin effects on vascular function in human atherosclerosis remain unclear. We examined the direct effects of atorvastatin on tetrahydrobiopterin-mediated endothelial nitric oxide (NO) synthase coupling in patients with coronary artery disease.
  
  
  RESULTS
  We first examined the association of statin treatment with vascular NO bioavailability and arterial superoxide (O(2)(·-)) in 492 patients undergoing coronary artery bypass graft surgery. Then, 42 statin-naïve patients undergoing elective coronary artery bypass graft surgery were randomized to atorvastatin 40 mg/d or placebo for 3 days before surgery to examine the impact of atorvastatin on endothelial function and O(2)(·-) generation in internal mammary arteries. Finally, segments of internal mammary arteries from 26 patients were used in ex vivo experiments to evaluate the statin-dependent mechanisms regulating the vascular redox state. Statin treatment was associated with improved vascular NO bioavailability and reduced O(2)(·-) generation in internal mammary arteries. Oral atorvastatin increased vascular tetrahydrobiopterin bioavailability and reduced basal and N-nitro-l-arginine methyl ester-inhibitable O(2)(·-) in internal mammary arteries independently of low-density lipoprotein lowering. In ex vivo experiments, atorvastatin rapidly improved vascular tetrahydrobiopterin bioavailability by upregulating GTP-cyclohydrolase I gene expression and activity, resulting in improved endothelial NO synthase coupling and reduced vascular O(2)(·-). These effects were reversed by mevalonate, indicating a direct effect of vascular hydroxymethylglutaryl-coenzyme A reductase inhibition.
  
  
  CONCLUSIONS
  This study demonstrates for the first time in humans the direct effects of statin treatment on the vascular wall, supporting the notion that this effect is independent of low-density lipoprotein lowering. Atorvastatin directly improves vascular NO bioavailability and reduces vascular O(2)(·-) through tetrahydrobiopterin-mediated endothelial NO synthase coupling. These findings provide new insights into the mechanisms mediating the beneficial vascular effects of statins in humans.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT01013103.
authors: Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital OX3 9DU, Oxford, UK.
authors: Charalambos
authors: C
authors: Antoniades
authors: Constantinos
authors: C
authors: Bakogiannis
authors: Paul
authors: P
authors: Leeson
authors: Tomasz J
authors: TJ
authors: Guzik
authors: Mei-Hua
authors: MH
authors: Zhang
authors: Dimitris
authors: D
authors: Tousoulis
authors: Alexios S
authors: AS
authors: Antonopoulos
authors: Michael
authors: M
authors: Demosthenous
authors: Kyriakoula
authors: K
authors: Marinou
authors: Ashley
authors: A
authors: Hale
authors: Andreas
authors: A
authors: Paschalis
authors: Costas
authors: C
authors: Psarros
authors: Costas
authors: C
authors: Triantafyllou
authors: Jennifer
authors: J
authors: Bendall
authors: Barbara
authors: B
authors: Casadei
authors: Christodoulos
authors: C
authors: Stefanadis
authors: Keith M
authors: KM
authors: Channon
mesh_terms: D000368:Aged; D000069059:Atorvastatin; D001682:Biological Availability; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D001026:Coronary Artery Bypass; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000601:surgery; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism*; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010084:Oxidation-Reduction; D058451:Oxidative Coupling / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; D000069059:Atorvastatin; D052250:Nitric Oxide Synthase Type III; C003402:sapropterin; D010100:Oxygen