title: Statin treatment upregulates vascular neuronal nitric oxide synthase through Akt/NF-kappaB pathway.
abstract: OBJECTIVE
  Three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are known to enhance vascular expression of endothelial (eNOS) and inducible nitric oxide synthase (iNOS). In this study, we examined whether statins also upregulate vascular expression of neuronal NOS (nNOS).
  
  
  RESULTS
  In cultured rat aortic smooth muscle cells, treatment with atorvastatin significantly increased nNOS expression, associated with activation of Akt and NF-kappaB. Inhibition of Akt by dominant-negative Akt suppressed atorvastatin-induced nNOS expression as well as Akt and NF-kappaB activation. Inhibition of NF-kappaB by dominant-negative IkappaB also attenuated atorvastatin-induced nNOS expression and NF-kappaB activation, but not Akt activation. We further examined whether atorvastatin also enhances nNOS expression in isolated mouse aorta, and if so, how much nNOS-derived NO accounts for atorvastatin-induced NOx production. In isolated aortas of wild-type mice, atorvastatin significantly increased all three NOS isoform expression and NOx production. In isolated aortas of doubly i/eNOS(-/-), n/eNOS(-/-), and n/iNOS(-/-) mice, which express only nNOS, iNOS, and eNOS, respectively, atorvastatin-induced NOx production was approximately 25%, 25%, and 50% to that of wild-type mice, respectively, suggesting that nNOS accounts for 25% of the atorvastatin-mediated NOx production.
  
  
  CONCLUSIONS
  These results indicate that atorvastatin upregulates vascular nNOS through Akt/NF-kappaB pathway, demonstrating a novel nNOS-mediated vascular effect of the statin.
authors.affiliation: Second Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Sei
authors.initials: S
authors.lastname: Nakata
authors.forename: Masato
authors.initials: M
authors.lastname: Tsutsui
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamashita
authors.forename: Akihide
authors.initials: A
authors.lastname: Tanimoto
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tasaki
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ozumi
authors.forename: Ken
authors.initials: K
authors.lastname: Sabanai
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Morishita
authors.forename: Osamu
authors.initials: O
authors.lastname: Suda
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Hirano
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sasaguri
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Nakashima
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yanagihara
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000069059:Atorvastatin; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000502:physiology*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: D019332:Endothelin-1; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D011758:Pyrroles; D000804:Angiotensin II; D009569:Nitric Oxide; D000069059:Atorvastatin; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051058:Oncogene Protein v-akt; D008798:Mevalonic Acid