Aldose reductase mediates endotoxin-induced production of nitric oxide and cytotoxicity in murine macrophages
Aldose reductase mediates endotoxin-induced production of nitric oxide and cytotoxicity in murine macrophages
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DOI：
10.1016/j.freeradbiomed.2007.01.033
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发表时间：
2007-04-15
影响因子：
7.4
通讯作者：
Srivastava, Satish K.
中科院分区：
文献类型：
--
作者：
Ramana, Kota V.;Reddy, Aramati B. M.;Srivastava, Satish K.
醛糖还原酶（AR）是一种普遍表达的蛋白，具有多营养作用，是毒性脂质醛还原的有效催化剂，也是引起继发性糖尿病并发症的高血糖、细胞因子和生长因子诱导的氧化还原敏感信号的中介。虽然AR抑制已被证明对氧化应激信号具有保护作用，但AR在调节一氧化氮（NO）合成和NO介导的细胞凋亡中的作用迄今尚未阐明。因此，我们研究了AR在调节脂多糖（LPS）诱导的RAW 264.7巨噬细胞NO合成和凋亡中的作用。抑制或RNA干扰消融AR抑制lps刺激No的产生和iNOS mRNA的过表达。抑制或消融AR也能阻止lps诱导的细胞凋亡、细胞周期阻滞、capase-3、p38-MAPK、INK、NF-kappa B和AP1的激活。此外，AR抑制抑制了lps诱导的巨噬细胞Bcl-x1下调和Bax、Bak上调。l -精氨酸升高，L-NAME降低LPS引起的细胞死亡的严重程度，而AR抑制剂则阻止细胞死亡。此外，抑制AR可防止HNE和GS-14NE引起的细胞死亡，但对GS-DHN没有作用。我们的研究结果首次表明ar催化的脂质醛-谷胱甘肽偶联物调节lps诱导的炎症标志物NO的产生和RAW 264.7细胞的细胞毒性。抑制或消融AR活性可能是内毒素血症和其他炎症性疾病的潜在治疗靶点。(c) 2007爱思唯尔公司版权所有。
Aldose reductase (AR) is a ubiquitously expressed protein with pleiotrophic roles as an efficient catalyst for the reduction of toxic lipid aldehydes and mediator of hyperglycemia, cytokine, and growth factor-induced redox-sensitive signals that cause secondary diabetic complications. Although AR inhibition has been shown to be protective against oxidative stress signals, the role of AR in regulating nitric oxide (NO) synthesis and NO-mediated apoptosis has not been elucidated to date. We therefore investigated the role of AR in regulating lipopolysaccharide (LPS)-induced NO synthesis and apoptosis in RAW 264.7 macrophages. Inhibition or RNA interference ablation of AR suppressed LPS-stimulated production of No and overexpression of iNOS mRNA. Inhibition or ablation of AR also prevented the LPS-induced apoptosis, cell cycle arrest, activation of capase-3, p38-MAPK, INK, NF-kappa B, and AP1. In addition, AR inhibition prevented the LPS-induced down-regulation of Bcl-x1 and up-regulation of Bax and Bak in macrophages. L-Arginine increased and L-NAME decreased the severity of cell death caused by LPS and AR inhibitors prevented it. Furthermore, inhibition of AR prevents cell death caused by HNE and GS-14NE, but not GS-DHN. Our findings for the first time suggest that AR-catalyzed lipid aldehyde-glutathione conjugates regulate the LPS-induced production of inflammatory marker NO and cytotoxicity in RAW 264.7 cells. Inhibition or ablation of AR activity may be a potential therapeutic target in endotoximia and other inflammatory diseases. (c) 2007 Elsevier Inc. All rights reserved.