Studies on the regulation of inducible nitric oxide synthase (iNOS) induction with statins in liver injury

他汀类药物诱导诱导型一氧化氮合酶（iNOS）诱导肝损伤的研究

基本信息

批准号：
17591447
负责人：
MATSUI Yoichi
金额：
$ 2.18万
依托单位：
Kansai Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591447/
关键词：
pitavastatin HMG-CoA reductase inhibitor nitric oxide inducible nitric oxide synthase cirrhosis primary cultured rat hepatocyte mRNA stabilizatio statins HMG-CoA reductase inhibitor nitric oxide inducible nitric oxide synthase mRNA s

项目摘要

Studies have indicated that protective effects of statins (HMG-CoA reductase inhibitor) are associated with the regulation of endothelial nitric oxide synthase (eNOS) or inducible NOS (iNOS) in heart and liver diseases. Statins have been reported to enhance hepatic NO production and decrease the vascular tone in patients with cirrhosis. However, it is unclear which NOS contributes to the increased NO production. We hypothesized that statins are involved in the up-regulation of iNOS in inflammatory liver, resulting in decreased hepatic resistance. Primary cultured rat hepatocytes were treated with pro-inflammatory cytokine interleukin (IL)-1β in the presence or absence of pitavastatin. Pretreatment of cells with pitavastatin resulted in up-regulation of iNOS induction by IL-1β, followed by increased NO production. Pitavastatin had no effects on the degradation of Iκ B or activation of NF-κB. However, pitavastatin super-induced the up-regulation of type I IL-1 receptor (IL-1 RI), which is essential for iNOS induction in addition to the Iκ B/NF-κB pathway. Mevalonate and geranylgeranylpyrophosphate blocked the stimulatory effects of pitavastatin on iNOS and IL-1 RI induction. Transfection experiments revealed that pitavastatin increased the stability of iNOS mRNA rather than its promoter transactivation. In support of this observation, pitavastatin increased the antisense-transcript corresponding to the 3'UTR of iNOS mRNA, which stabilizes iNOS mRNA by interacting with the 3'UTR and RNA-binding proteins. These findings demonstrate that pitavastatin up-regulates iNOS by the stabilization of its mRNA, presumably through the super-induction of IL-1 RI and antisense-transcript. Statins may contribute to a novel potentiated treatment in liver injuries including cirrhosis.

研究表明，他汀类药物（HMG-COA还原酶抑制剂）受保护的作用与心脏和肝脏疾病中内皮一氧化氮合酶（ENOS）或可诱导的NOS（INOS）的调节有关。据报道，他汀类药物可以增强肝硬化的肝脏NO产生并降低肝硬化患者的血管张力。但是，目前尚不清楚哪个NOS有助于提高无生产力。我们假设他汀类药物参与炎症性肝脏中iNOS的上调，从而降低了肝耐药性。在存在或不存在pitavastatin的情况下，将原代培养的大鼠肝细胞用促炎性细胞因子白介素（IL）-1β处理。对pitavastatin的细胞进行预处理导致IL-1β诱导iNOS诱导的上调，然后无产生增加。 Pitavastatin对IκB的降解或NF-κB的激活没有影响。然而，pitavastatin超级引起的I型IL-1受体（IL-1 RI）的上调，这对于INOS诱导外，除了IκB/NF-κB途径外，这对于iNOS诱导至关重要。甲瓦隆酸盐和黄烷基戊酰磷酸磷酸盐阻断了pitavastatin对iNOS和IL-1 RI诱导的刺激作用。转染实验表明，pitavastatin提高了iNOS mRNA的稳定性，而不是其启动子的反式激活。为了支持这一观察，pitavastatin增加了与Inos mRNA的3'UTR相对应的反义转录，该反义mRNA的3'UTR通过与3'UTR和RNA结合蛋白相互作用来稳定INOS mRNA。这些发现表明，pitavastatin通过其mRNA的稳定来上调INOS，这大概是通过IL-1 RI和反义转录的超级诱导。他汀类药物可能会导致肝损伤的新型潜在治疗方法。

项目成果

期刊论文数量（57）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Clinical impact of multi-detector row CT on patients with pancreatic cancer.

多排CT对胰腺癌患者的临床影响。

DOI：
发表时间：
2007
期刊：
Pancreas 34(2)
影响因子：
0
作者：
Satoi S;Yamamoto H
通讯作者：
Yamamoto H

Influence of transcatheter arterial chemoembolization on the prognosis after hepatectomy for hepatocellular carcinoma in patients with severe liver dysfunction.

DOI：
发表时间：
2006-09
期刊：
Anticancer research
影响因子：
2
作者：
M. Kaibori;N. Tanigawa;Y. Matsui;Takamichi Saito;Y. Uchida;M. Ishizaki;Hironori Tanaka;Y. Kamiyama
通讯作者：
M. Kaibori;N. Tanigawa;Y. Matsui;Takamichi Saito;Y. Uchida;M. Ishizaki;Hironori Tanaka;Y. Kamiyama

Enhanced production of IL-6 in peripheral blood monocytes stimulated with mucins secreted into the bloodstream.

分泌到血流中的粘蛋白刺激外周血单核细胞中 IL-6 的产生增强。