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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).

METHODS AND 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+Show Affiliations

Second Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17082483

Citation

Nakata, Sei, et al. "Statin Treatment Upregulates Vascular Neuronal Nitric Oxide Synthase Through Akt/NF-kappaB Pathway." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 1, 2007, pp. 92-8.
Nakata S, Tsutsui M, Shimokawa H, et al. Statin treatment upregulates vascular neuronal nitric oxide synthase through Akt/NF-kappaB pathway. Arterioscler Thromb Vasc Biol. 2007;27(1):92-8.
Nakata, S., Tsutsui, M., Shimokawa, H., Yamashita, T., Tanimoto, A., Tasaki, H., ... Yanagihara, N. (2007). Statin treatment upregulates vascular neuronal nitric oxide synthase through Akt/NF-kappaB pathway. Arteriosclerosis, Thrombosis, and Vascular Biology, 27(1), pp. 92-8.
Nakata S, et al. Statin Treatment Upregulates Vascular Neuronal Nitric Oxide Synthase Through Akt/NF-kappaB Pathway. Arterioscler Thromb Vasc Biol. 2007;27(1):92-8. PubMed PMID: 17082483.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Statin treatment upregulates vascular neuronal nitric oxide synthase through Akt/NF-kappaB pathway. AU - Nakata,Sei, AU - Tsutsui,Masato, AU - Shimokawa,Hiroaki, AU - Yamashita,Takahiro, AU - Tanimoto,Akihide, AU - Tasaki,Hiromi, AU - Ozumi,Kiyoshi, AU - Sabanai,Ken, AU - Morishita,Tsuyoshi, AU - Suda,Osamu, AU - Hirano,Hideyasu, AU - Sasaguri,Yasuyuki, AU - Nakashima,Yasuhide, AU - Yanagihara,Nobuyuki, Y1 - 2006/11/02/ PY - 2006/11/4/pubmed PY - 2007/1/24/medline PY - 2006/11/4/entrez SP - 92 EP - 8 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler. Thromb. Vasc. Biol. VL - 27 IS - 1 N2 - 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). METHODS AND 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. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/17082483/Statin_treatment_upregulates_vascular_neuronal_nitric_oxide_synthase_through_Akt/NF_kappaB_pathway_ L2 - http://www.ahajournals.org/doi/full/10.1161/01.ATV.0000251615.61858.33?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -