The lipid peroxidation product 4-hydroxy-2-nonenal induces tissue factor decryption via ROS generation and the thioredoxin system
The lipid peroxidation product 4-hydroxy-2-nonenal induces tissue factor decryption via ROS generation and the thioredoxin system
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DOI：
10.1182/bloodadvances.2017010132
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发表时间：
2017-11-28
期刊：
影响因子：
7.5
通讯作者：
Rao, L. Vijaya Mohan
中科院分区：
文献类型：
--
作者：
Ansari, Shabbir A.;Pendurthi, Usha R.;Rao, L. Vijaya Mohan
许多病理生理因子将细胞上的隐组织因子（TF）转化为血栓形成前的TF，其中一种刺激是4-羟基-2-壬烯醛（HNE），这是由omega-6多不饱和脂肪酸氧化产生的最丰富的醛。HNE被证明可以诱导活性氧（ROS）的产生和p38 MAPK的激活，但它们之间的联系及其在TF解密中的作用尚不清楚。本研究旨在阐明单核细胞中hne诱导的TF解密的潜在机制。本文提供的数据表明，线粒体是hne诱导的ROS生成的主要来源。抑制线粒体电子传递链复合体III和V可阻断hne诱导的ROS生成，但不能阻断p38 MAPK的激活。这些抑制剂显著降低磷脂酰丝氨酸（PS）外化和TF解密，但不完全。HNE处理抑制了不依赖ROS的硫氧还蛋白还原酶（TrxR）和硫氧还蛋白（Trx）的活性。HNE或药理学抑制剂抑制TrxR/Trx系统可诱导p38 MAPK激活、PS外化和TF解密。进一步的研究表明，TrxR/Trx的抑制导致凋亡信号调节激酶（ASK-1）和丝裂原活化蛋白激酶激酶3/6的激活。小干扰RNA抑制ASK-1表达或药理学抑制剂抑制其活性可减少hne诱导的TF解密。总的来说，我们的数据表明HNE通过两种不同的途径诱导TF解密。一个依赖于ROS，但不依赖于p38 MAPK的激活，另一个通过TrxR/Trx，依赖于p38 MAPK的激活。然而，这两种机制都会导致负责TF解密的外层页的PS增强。
Many pathophysiologic agents transform cryptic tissue factor (TF) on cells to prothrombotic TF, and one such stimulus is 4-hydroxy-2-nonenal (HNE), the most abundant aldehyde produced by the oxidation of omega-6 polyunsaturated fatty acids. HNE was shown to induce reactive oxygen species (ROS) generation and p38 MAPK activation, but the link between them and their role in TF decryption are unclear. The present study was carried out to elucidate potential mechanisms involved in HNE-induced TF decryption in monocytic cells. The data presented herein show that mitochondria are the primary source for HNE-induced ROS generation. The inhibition of mitochondrial electron transport chain complex III and V blocked HNE-induced ROS generation, but not p38 MAPK activation. These inhibitors reduced phosphatidylserine (PS) externalization and TF decryption significantly, but not completely. HNE treatment inhibited the activities of thioredoxin reductase (TrxR) and thioredoxin (Trx), independent of ROS. Inhibition of the TrxR/Trx system by HNE or pharmacological inhibitors induced p38 MAPK activation, PS externalization, and TF decryption. Additional studies revealed that the inhibition of TrxR/Trx led to activation of apoptosis signal-regulating kinase (ASK-1) and mitogen-activated protein kinase kinase 3/6. Inhibition of ASK-1 expression by small interfering RNA or its activity by pharmacological inhibitors diminished HNE-induced TF decryption. Overall, our data suggest that HNE induces TF decryption by 2 distinctive pathways. One is ROS dependent but independent of p38 MAPK activation, and the other is via TrxR/Trx and is p38 MAPK activation dependent. However, both mechanisms result in the enhancement of PS at the outer leaflet that is responsible for TF decryption.