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
Second Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Arterioscler Thromb Vasc Biol. 2007 Jan;27(1):92-8. doi: 10.1161/01.ATV.0000251615.61858.33. Epub 2006 Nov 2.
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).
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.
These results indicate that atorvastatin upregulates vascular nNOS through Akt/NF-kappaB pathway, demonstrating a novel nNOS-mediated vascular effect of the statin.
已知3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（他汀类药物）可增强血管内皮型一氧化氮合酶（eNOS）和诱导型一氧化氮合酶（iNOS）的表达。在本研究中，我们检测了他汀类药物是否也能上调血管中神经元型一氧化氮合酶（nNOS）的表达。
在培养的大鼠主动脉平滑肌细胞中，阿托伐他汀处理显著增加nNOS表达，这与Akt和核因子κB（NF-κB）的激活相关。用显性负性Akt抑制Akt可抑制阿托伐他汀诱导的nNOS表达以及Akt和NF-κB的激活。用显性负性IκB抑制NF-κB也减弱了阿托伐他汀诱导的nNOS表达和NF-κB激活，但不影响Akt激活。我们进一步检测了阿托伐他汀是否也能增强分离的小鼠主动脉中nNOS的表达，如果是，nNOS衍生的一氧化氮对阿托伐他汀诱导的氧化氮（NOx）产生有多大贡献。在野生型小鼠的分离主动脉中，阿托伐他汀显著增加了所有三种一氧化氮合酶同工型的表达和NOx产生。在分别仅表达nNOS、iNOS和eNOS的双基因敲除i/eNOS(-/-)、n/eNOS(-/-)和n/iNOS(-/-)小鼠的分离主动脉中，阿托伐他汀诱导的NOx产生分别约为野生型小鼠的25%、25%和50%，这表明nNOS占阿托伐他汀介导的NOx产生的25%。
这些结果表明，阿托伐他汀通过Akt/NF-κB途径上调血管nNOS，证明了他汀类药物一种新的由nNOS介导的血管效应。
