HMG-CoA reductase inhibitors inhibit inducible nitric oxide synthase gene expression in macrophages
HMG-CoA reductase inhibitors inhibit inducible nitric oxide synthase gene expression in macrophages
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DOI：
10.1159/000071159
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发表时间：
2003-07-01
影响因子：
11
通讯作者：
Lin, WW
中科院分区：
文献类型：
--
作者：
Huang, KC;Chen, CW;Lin, WW
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，是胆固醇合成的有效抑制剂，在心血管疾病中具有广泛的治疗用途。然而，最近的证据表明，他汀类药物的有益作用可能超出其对血清胆固醇水平的作用。在这项研究中，我们研究了洛伐他汀，普伐他汀，阿托伐他汀和氟伐他汀对小鼠RAW 264.7细胞巨噬细胞生成一氧化氮（NO）的影响。用脂多糖（LIPS）和干扰素-γ（IFN-γ）刺激巨噬细胞导致诱导型NO合酶（iNOS）表达，这伴随着大量的NO形成。在0.1-30 μ M浓度下，他汀类药物可不同程度地抑制刺激诱导的NO生成和iNOS诱导。这种抑制作用发生在转录水平上，并且表现出的效力顺序为洛伐他汀>阿托伐他汀>氟伐他汀，比普伐他汀大得多。我们发现，LPS诱导的IkappaB激酶和核因子-κ B（NF-κ B）的激活，以及IFN-γ诱导的信号转导和转录激活因子1（STAT 1）的磷酸化，减少洛伐他汀。此外，抑制洛伐他汀的NO生成和kappaB激活被逆转甲羟戊酸，香叶基香叶基焦磷酸和法呢焦磷酸。所有这些结果表明，他汀类药物对iNOS基因表达的抑制可以归因于干扰蛋白质异戊二烯化，其介导了iNOS基因转录上游信号通路中的NF-κ B和STAT 1活化。版权所有（C）2003国家科学理事会，中华民国和S. Karger AG，巴塞尔。
The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, statins, are potent inhibitors of cholesterol synthesis and have wide therapeutic use in cardiovascular diseases. Recent evidence, however, suggests that the beneficial effects of statins may extend beyond their action on serum cholesterol levels. In this study, we investigated the effects of lovastatin, pravastatin, atorvastatin and fluvastatin on macrophage formation of nitric oxide (NO) in murine RAW 264.7 cells. Stimulation of macrophages with lipopolysaccharide (LIPS) and interferon-gamma (IFN-gamma) resulted in inducible NO synthase (iNOS) expression, which was accompanied by a large amount of NO formation. At concentrations of 0.1-30 muM, statins can inhibit stimuli-induced NO formation and iNOS induction to different extents. This inhibition occurs at the transcriptional level, and displays potency in the order of lovastatin > atorvastatin > fluvastatin much greater than pravastatin. We found that LPS-induced IkappaB kinase and nuclear factor-kappaB (NF-kappaB) activation, as well as IFN-gamma-induced signal transducer and activator of transcription 1 (STAT1) phosphorylation, were reduced by lovastatin. Moreover, inhibition by lovastatin of NO production and kappaB activation was reversed by mevalonate, geranylgeranyl pyrophosphate and farnesyl pyrophosphate. All these results suggest that inhibition of iNOS gene expression by statins can be attributed to interference with protein isoprenylation, which mediates both NF-kappaB and STAT1 activation in the upstream signaling pathways for iNOS gene transcription. Copyright (C) 2003 National Science Council, ROC and S. Karger AG, Basel.