Inhibition of inducible nitric oxide synthase prevents lipid peroxidation in osteoarthritic chondrocytes
Inhibition of inducible nitric oxide synthase prevents lipid peroxidation in osteoarthritic chondrocytes
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DOI：
10.1002/jcb.24096
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发表时间：
2012-07-01
影响因子：
4
通讯作者：
Benderdour, Mohamed
中科院分区：
文献类型：
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作者：
Bentz, Mireille;Zaouter, Charlotte;Benderdour, Mohamed
一氧化氮（NO）和脂质过氧化（LPO）产物4-羟基壬烯醛（HNE）被认为是骨关节炎（OA）中软骨破坏的关键介质。还已知NO是通过过氧亚硝酸盐形成引发LPO的重要中间体。本研究的目的是评估诱导型NO合酶（iNOS）抑制剂N-亚氨基乙基-L-赖氨酸（L-NIL）通过抑制人OA软骨细胞和软骨外植体中的NO来防止HNE生成的能力。人OA软骨细胞和软骨外植体用L-NIL处理，然后用或不用细胞毒性或非细胞毒性浓度的白细胞介素-1 β（IL-1 β）或HNE处理。与氧化应激，细胞凋亡，炎症，和catalysts相关的参数进行了研究。L-NIL以剂量依赖性方式抑制IL-1 β诱导的NO释放、iNOS活性、硝化蛋白和HNE生成。它还阻断了IL-1 β诱导的HNE代谢谷胱甘肽-S-转移酶（GST）的失活。L-NIL恢复了OA软骨外植体中的HNE和GSTA 4 -4水平。有趣的是，它还消除了IL-1 β诱导的活性氧（ROS）生成和p47 NADPH氧化酶激活。此外，L-NIL显着衰减细胞死亡和凋亡的标志物引起的暴露于细胞毒性剂量的HNE，以及释放前列腺素E2和金属蛋白酶-13诱导的非细胞毒性剂量的HNE。总之，我们的研究结果支持L-NIL在OA中的有益作用，通过（i）通过NO依赖性和/或非依赖性机制阻止LPO过程和ROS产生，以及（ii）减弱HNE诱导的细胞死亡和软骨损伤的不同介质。J.细胞。113：22562267，2012。(c)2012 Wiley Periodicals，Inc.
Nitric oxide (NO) and the lipid peroxidation (LPO) product 4-hydroxynonenal (HNE) are considered to be key mediators of cartilage destruction in osteoarthritis (OA). NO is also known to be an important intermediary in LPO initiation through peroxynitrite formation. The aim of the present study was to assess the ability of the inducible NO synthase (iNOS) inhibitor N-iminoethyl-L-lysine (L-NIL) to prevent HNE generation via NO suppression in human OA chondrocytes and cartilage explants. Human OA chondrocytes and cartilage explants were treated with L-NIL and thereafter with or without interleukin-1beta (IL-1 beta) or HNE at cytotoxic or non-cytotoxic concentrations. Parameters related to oxidative stress, apoptosis, inflammation, and catabolism were investigated. L-NIL stifled IL-1 beta-induced NO release, iNOS activity, nitrated proteins, and HNE generation in a dose-dependent manner. It also blocked IL-1 beta-induced inactivation of the HNE-metabolizing glutathione-s-transferase (GST). L-NIL restored both HNE and GSTA4-4 levels in OA cartilage explants. Interestingly, it also abolished IL-1 beta-evoked reactive oxygen species (ROS) generation and p47 NADPH oxidase activation. Furthermore, L-NIL significantly attenuated cell death and markers of apoptosis elicited by exposure to a cytotoxic dose of HNE as well as the release of prostaglandin E2 and metalloproteinase-13 induced by a non-cytotoxic dose of HNE. Altogether, our findings support a beneficial effect of L-NIL in OA by (i) preventing the LPO process and ROS production via NO-dependent and/or independent mechanisms and (ii) attenuating HNE-induced cell death and different mediators of cartilage damage. J. Cell. Biochem. 113: 22562267, 2012. (c) 2012 Wiley Periodicals, Inc.