S tatin enhances cytokine-mediated induction of nitric oxide synthesis in vascular smooth muscle cells
S tatin enhances cytokine-mediated induction of nitric oxide synthesis in vascular smooth muscle cells
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他汀类药物增强血管平滑肌细胞细胞因子介导的一氧化氮合成诱导
DOI：
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
K. Kasai
中科院分区：
文献类型：
--
作者：
Y. Hattori;N. Nakanishi;K. Kasai
目的：我们研究了他汀类药物西立伐他汀和氟伐他汀对白细胞介素-1b（IL-1）或与干扰素-g（IFN）联合刺激的血管平滑肌细胞（VSMC）诱导一氧化氮（NO）产生的影响。研究方法：我们检测了NO释放，诱导型NO合酶（iNOS）的mRNA和蛋白水平，iNOS基因转录率，和iNOS mRNA的稳定性在精氨酸激活的VSMC。我们还评估了核因子（NF）-kB活性和四氢生物蝶呤（BH 4）的合成。结果：两种他汀类药物均能剂量依赖性地增强细胞因子诱导的NO生成。IL-1 / IFN刺激VSMC诱导型一氧化氮合酶mRNA和蛋白表达。两种他汀类药物均显著上调IL-1 /IFN刺激的iNOS mRNA和蛋白表达，并增强iNOS基因转录，如核运行试验所示。但它们并不改变iNOS mRNA的稳定性。这两种他汀类药物轻微调制IL-1 /IFN诱导的NF-κ B激活，这是不相关的NO生产的影响。细胞因子诱导VSMC中BH 4的从头合成。这一事件是必不可少的诱导NO合成，这需要转录诱导的基因，不仅编码iNOS，而且鸟苷三磷酸环水解酶I（GTPCH），第一和限速酶从头BH 4合成。两种他汀类药物均能增强IL-1 / IFN诱导的BH 4和GTPCH mRNA的合成。外源性甲羟戊酸显着防止和香叶基香叶基焦磷酸逆转两种他汀类药物的刺激作用。此外，香叶基香叶基转移酶I抑制剂GGTI-298显著增加IL-1 /IFN诱导的NO产生。结论：我们的数据表明，他汀类药物增强免疫刺激剂诱导的NO的生产增加iNOS基因表达在转录水平上通过NF-κ B的非依赖性途径。他汀类药物对NO产生的影响至少部分是由于阻断甲羟戊酸的生物合成，这阻止了类异戊二烯的生物合成。除了增加iNOS表达，他汀类药物增强GTPCH基因表达和BH 4合成，从而防止BH 4的相对短缺，这可能改变NOS催化的保护性NO和有害活性氧之间的平衡。© 2002 Elsevier Science B. V.保留所有权利。
Objective: We investigated the effects of the statins, cerivastatin and fluvastatin, on the induction of nitric oxide (NO) production in vascular smooth muscle cells (VSMC) stimulated by interleukin-1b (IL-1) or in combination with interferon-g (IFN). Methods: We measured NO release, inducible NO synthase (iNOS) mRNA and protein levels, iNOS gene transcription rates, and iNOS mRNA stabilities in cytokine-activated VSMC. We also evaluated nuclear factor (NF)-kB activity and tetrahydrobiopterin (BH4) synthesis. Results: NO production induced by cytokines was dose-dependently enhanced by both statins. Incubating VSMC with IL-1 / IFN stimulated iNOS mRNA and protein expression. Both statins significantly upregulated IL-1 / IFN-stimulated iNOS mRNA and protein expression, and enhanced iNOS gene transcription as shown by nuclear run-on assays. However, they did not alter the stability of iNOS mRNA. Both statins slightly modulated IL-1 / IFN-induced NF-kB activation, which was not associated with their effect on NO production. Cytokines induce the de novo synthesis of BH4 in VSMC. This event is essential for the induction of NO synthesis, which requires transcriptional induction of the genes that encode not only iNOS but also guanosine triphosphate cyclohydrolase I (GTPCH), the first and rate-limiting enzyme in de novo BH4 synthesis. The synthesis of BH4 and GTPCH mRNA induced by IL-1 / IFN were enhanced by both statins. Exogenous mevalonate significantly prevented and geranylgeranylpyrophosphate reversed the stimulatory effect of both statins. Furthermore, the geranylgeranyltransferase I inhibitor GGTI-298 significantly increased IL-1 / IFN-induced NO production. Conclusion: Our data demonstrated that statins enhance immunostimulants-induced NO production by increasing iNOS gene expression at the transcriptional level via an NF-kB-independent pathway. The effect of statins on NO production is due at least partly through blocking the biosynthesis of mevalonate, which prevents isoprenoid biosynthesis. In addition to augmenting iNOS expression, statins potentiate GTPCH gene expression and BH4 synthesis, thereby preventing a relative shortage of BH4 which may shift the balance between NOS-catalyzed generation of protective NO and deleterious reactive oxygen species. 2002 Elsevier Science B.V. All rights reserved.
DOI：
10.1016/s0021-9258(17)36703-0
发表时间：
1994-05
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
C. Nathan;Q. Xie
通讯作者：
C. Nathan;Q. Xie
L-精氨酸可预防 LDL 受体敲除小鼠中的黄瘤发展并抑制动脉粥样硬化。
影响因子：
37.8
作者：
Aji,W;Ravalli,S;Szabolcs,M;Jiang,XC;Sciacca,RR;Michler,RE;Cannon,PJ
通讯作者：
Cannon,PJ
影响因子：
15.9
作者：
Shears, LL;Kawaharada, N;Pham, SM
通讯作者：
Pham, SM