α-lipoic acid-induced heme oxygenase-1 expression is mediated by nuclear factor erythroid 2-related factor 2 and p38 mitogen-activated protein kinase in human monocytic cells
α-lipoic acid-induced heme oxygenase-1 expression is mediated by nuclear factor erythroid 2-related factor 2 and p38 mitogen-activated protein kinase in human monocytic cells
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DOI：
10.1161/01.atv.0000183745.37161.6e
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发表时间：
2005-10-01
影响因子：
8.7
通讯作者：
O'Connell, MA
中科院分区：
文献类型：
--
作者：
Ogborne, RM;Rushworth, SA;O'Connell, MA
目的：血红素加氧酶-1(HO-1)是血红素分解代谢的限速酶，在血管系统中起着保护作用。HO-1诱导抑制巨噬细胞产生细胞因子。抗氧化剂可诱导不同类型细胞中HO-1的表达。α-硫辛酸(ALA)是一种含有硫醇的膳食抗氧化剂，在血管疾病中具有保护作用，在单核细胞中具有抗炎作用。方法与结果：ALA诱导THP-1细胞HO-1mRNA表达呈时间和剂量依赖性，4h达高峰，24h恢复至基线水平。这与HO-1蛋白表达增加有关。ALA刺激转录因子核因子-红系2相关因子2(NRF2)易位到细胞核，并在30分钟内与人HO-1抗氧化反应元件(ARE)结合。显性负性Nrf2抑制剂可使ALA诱导的HO-1mRNA表达减少66%。P38丝裂原活化蛋白激酶抑制剂SB203580可使ALA诱导的HO-1mRNA表达减少75%，并抑制ALA诱导的Nrf2与HO-1 ARE的结合。结论ALA通过Nrf2和p38诱导THP-1单核细胞HO-1表达。ALA对单核细胞的保护作用是否由HO-1介导，尚需进一步研究。
Objective - Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, plays a protective role in the vascular system. HO-1 induction inhibits cytokine production in macrophages. Antioxidants induce HO-1 expression in various cell types. alpha-lipoic acid (ALA), a thiol-containing dietary antioxidant, exhibits protective effects in vascular disease and induces anti-inflammatory effects in monocytes. This study examined the effects of ALA on HO-1 expression in human monocytic cells.Methods and Results - ALA time and dose-dependently induced HO-1 mRNA expression in THP-1 cells, with peak expression at 4 hours and returning to baseline by 24 hours. This correlated with an increase in HO-1 protein expression. ALA stimulated translocation of the transcription factor nuclear factor-erythroid 2 - related factor 2 (Nrf2) into the nucleus and binding to a human HO-1 antioxidant response element ( ARE) by 30 minutes. A dominant-negative Nrf2 inhibitor reduced ALA-induced HO-1 mRNA expression by 66%. Pretreatment with SB203580, a p38 mitogen-activated protein kinase inhibitor, reduced ALA-induced HO-1 mRNA expression by 75% and inhibited ALA-induced Nrf2 binding to the HO-1 ARE.Conclusions - These results demonstrate that ALA induces HO-1 expression in THP-1 monocytic cells via Nrf2 and p38. Further studies are required to investigate whether the protective effects of ALA in monocytes are mediated by HO-1.