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

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 27; no. 1; pp. 92 - 98
• Main Authors: Nakata, Sei, Tsutsui, Masato, Shimokawa, Hiroaki, Yamashita, Takahiro, Tanimoto, Akihide, Tasaki, Hiromi, Ozumi, Kiyoshi, Sabanai, Ken, Morishita, Tsuyoshi, Suda, Osamu, Hirano, Hideyasu, Sasaguri, Yasuyuki, Nakashima, Yasuhide, Yanagihara, Nobuyuki
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.01.2007; Hagerstown, MD Lippincott
• Subjects: Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Coronary heart disease; Diseases of the cardiovascular system; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Heart; Medical sciences; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); nuclear factor-KB; Enzyme; Cardiovascular disease; neuronal nitric oxide synthase; Statin derivative; Akt; Nitric-oxide synthase; Vascular disease; Treatment; Nitric oxide; statins; Atherosclerosis; Oxidoreductases; Antilipemic agent
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000251615.61858.33

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