Pitavastatin up-regulates the induction of iNOS through enhanced stabilization of its mRNA in pro-inflammatory cytokine-stimulated hepatocytes
Pitavastatin up-regulates the induction of iNOS through enhanced stabilization of its mRNA in pro-inflammatory cytokine-stimulated hepatocytes
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DOI：
10.1016/j.niox.2007.08.005
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发表时间：
2008-02-01
影响因子：
3.9
通讯作者：
Okumura, Tadayoshi
中科院分区：
文献类型：
--
作者：
Habara, Kozo;Hamada, Yoshinori;Okumura, Tadayoshi
研究表明，他汀类药物(HMG-CoA还原酶抑制剂)在心脏和肝脏疾病中的保护作用与内皮型一氧化氮合酶(ENOS)或诱导型一氧化氮合酶(INOS)的调节有关。据报道，他汀类药物可增加肝硬变患者肝脏NO的生成，降低血管紧张性。然而，目前还不清楚是哪种一氧化氮合酶导致了NO产量的增加。我们推测他汀类药物参与了炎症肝脏中iNOS的上调，导致肝脏阻力降低。原代培养的大鼠肝细胞在加入或不加入匹伐他汀的情况下，用促炎症细胞因子白介素1β处理。用匹伐他汀处理细胞后，IL-1β诱导的iNOS表达上调，NO产生增加。Pitavastatin对I-kappa B的降解和核因子-kappaB的激活均无影响，但他汀超诱导I型IL-1受体(IL-1RI)表达上调，而IL-1RI是诱导型一氧化氮合酶(INOS)的重要途径。甲羟戊酸和焦磷酸香叶酯可阻断匹伐他汀对诱导型一氧化氮合酶和IL-1RI的刺激作用。转染实验表明，匹伐他汀增加了iNOS mRNA的稳定性，而不是其启动子的反式激活。为了支持这一观察结果，匹伐他汀增加了与iNOS mRNA的3‘-UTR相对应的反义转录，通过与3’-UTR和RNA结合蛋白相互作用来稳定iNOS mRNA。这些结果表明，匹伐他汀通过稳定iNOS的mRNA，可能是通过过度诱导IL-1RI和反义转录来上调iNOS。这意味着他汀类药物可能有助于包括肝硬变在内的肝损伤的新的强化治疗。(C)2007 Elsevier Inc.保留所有权利。
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)-1 beta in the presence or absence of pitavastatin. Pretreatment of cells with pitavastatin resulted in up-regulation of iNOS induction by IL-1 beta, followed by increased NO production. Pitavastatin had no effects on the degradation Of I kappa B or activation of NF-kappa B. However, pitavastatin super-induced the up-regulation of type I IL-1 receptor (IL-1RI), which is essential for iNOS induction in addition to the I kappa B/NF-kappa B pathway. Mevalonate and geranylgeranylpyropbosphate blocked the stimulatory effects of pitavastatin on iNOS and IL-1RI 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-1RI and antisense-transcript. This implies that statins may contribute to a novel potentiated treatment in liver injuries including cirrhosis. (c) 2007 Elsevier Inc. All rights reserved.