Hsieh Ching-Hua, Jeng Seng-Feng, Hsieh Min-Wei, Chen Yi-Chun, Rau Cheng-Shyuan, Lu Tsu-Hsiang, Chen Shun-Sheng
Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Hsien, Taiwan.
Toxicol Sci. 2008 Mar;102(1):150-9. doi: 10.1093/toxsci/kfm298. Epub 2007 Dec 10.
With potentially neuroprotective properties, heme oxygenase-1 (HO-1) has been suggested to be the main mediator of cholesterol-independent anti-inflammatory and antioxidant actions of statins. However, we had demonstrated that simvastatin-induced HO-1 increased apoptosis of Neuro 2A cells in glucose deprivation, and iron production from HO-1 activity may be responsible for the toxicity. This study was designed to explore the effect of simvastatin-induced HO-1 on cultured Neuro 2A and C6 cells exposed to lipopolysaccharide (LPS). We found that the HO-1 upregulation was significantly associated with increased nuclear factor kappa B (NF-kappaB) activation, manifested as IkappaBalpha phosphorylation and p65 nuclear translocation, as well as increased production of superoxides. Inhibition of the induced HO-1 by zinc protoporphyrin reduced the increased NF-kappaB activation and superoxides production. RNA interference with HO-1 siRNA reduced the expression of HO-1 transcripts and protein as well as oxygen radical production. Addition of the iron chelator desferrioxamine to reduce the accumulation of ferric iron from heme by HO-1 resulted in blockade of the aggravated oxygen radical production. There was no significant effect on production of oxygen radicals under these conditions in the presence of a CO donor (RuCO) or a CO scavenger (hemoglobin). In addition, the viable cells were significantly decreased in 48 h in those cells receiving simvastatin pretreatment plus LPS compared to those in control or exposed to simvastatin or LPS alone. This study revealed that simvastatin-induced HO-1 led to increased NF-kappaB activation and superoxides production in the neuronal cells when exposed to LPS, and iron production may play a role in such a response.
由于具有潜在的神经保护特性，血红素加氧酶-1（HO-1）被认为是他汀类药物非胆固醇依赖性抗炎和抗氧化作用的主要介质。然而，我们已经证明，辛伐他汀诱导的HO-1会增加葡萄糖剥夺条件下Neuro 2A细胞的凋亡，并且HO-1活性产生的铁可能是毒性的原因。本研究旨在探讨辛伐他汀诱导的HO-1对暴露于脂多糖（LPS）的培养Neuro 2A和C6细胞的影响。我们发现，HO-1的上调与核因子κB（NF-κB）激活增加显著相关，表现为IκBα磷酸化和p65核转位，以及超氧化物产生增加。锌原卟啉对诱导的HO-1的抑制作用降低了NF-κB激活和超氧化物产生的增加。用HO-1 siRNA进行RNA干扰降低了HO-1转录本和蛋白质的表达以及氧自由基的产生。添加铁螯合剂去铁胺以减少HO-1从血红素中积累三价铁，导致加剧的氧自由基产生被阻断。在存在CO供体（RuCO）或CO清除剂（血红蛋白）的情况下，这些条件下对氧自由基的产生没有显著影响。此外，与单独接受对照、辛伐他汀或LPS处理的细胞相比，接受辛伐他汀预处理加LPS处理的细胞在48小时内活细胞显著减少。本研究表明，辛伐他汀诱导的HO-1在神经元细胞暴露于LPS时导致NF-κB激活增加和超氧化物产生增加，并且铁的产生可能在这种反应中起作用。
