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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:92.)
© 2007 American Heart Association, Inc.

Vascular Biology

Statin Treatment Upregulates Vascular Neuronal Nitric Oxide Synthase Through Akt/NF-B Pathway

Sei Nakata; Masato Tsutsui; Hiroaki Shimokawa; Takahiro Yamashita; Akihide Tanimoto; Hiromi Tasaki; Kiyoshi Ozumi; Ken Sabanai; Tsuyoshi Morishita; Osamu Suda; Hideyasu Hirano; Yasuyuki Sasaguri; Yasuhide Nakashima; Nobuyuki Yanagihara

From the Second Department of Internal Medicine (S.N., H.T., K.O., T.M., O.S., Y.N.) and Departments of Pharmacology (M.T., T.Y., K.S., N.Y.) and Pathology (A.T., Y.S.), School of Medicine, and Department of Environmental Management II (H.H.), School of Health Sciences, University of Occupational and Environmental Health, Kitakyushu; and the Department of Cardiovascular Medicine (H.S.), Tohoku University Graduate School of Medicine, Sendai, Japan.

Correspondence to Masato Tsutsui, MD, PhD, Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. E-mail mt2498{at}med.uoeh-u.ac.jp

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-B. Inhibition of Akt by dominant-negative Akt suppressed atorvastatin-induced nNOS expression as well as Akt and NF-B activation. Inhibition of NF-B by dominant-negative IB also attenuated atorvastatin-induced nNOS expression and NF-B 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-B pathway, demonstrating a novel nNOS-mediated vascular effect of the statin.

HMG-CoA reductase inhibitors (statins) are known to enhance vascular expression of endothelial and inducible nitric oxide synthase. Here we report that atorvastatin also upregulates vascular neuronal nitric oxide synthase through Akt/NF-B pathway, demonstrating a novel nNOS-mediated vascular effect of the statin.

Key Words: Akt • neuronal nitric oxide synthase • nitric oxide • nuclear factor-B • statins

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