Statin treatment upregulates vascular neuronal nitric oxide synthase through Akt/NF-kappaB pathway.
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.
Nakata
Sei
S
Second Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Tsutsui
Masato
M
Shimokawa
Hiroaki
H
Yamashita
Takahiro
T
Tanimoto
Akihide
A
Tasaki
Hiromi
H
Ozumi
Kiyoshi
K
Sabanai
Ken
K
Morishita
Tsuyoshi
T
Suda
Osamu
O
Hirano
Hideyasu
H
Sasaguri
Yasuyuki
Y
Nakashima
Yasuhide
Y
Yanagihara
Nobuyuki
N
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
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