Role of endoplasmic reticulum stress in acrolein-induced endothelial activation.
Role of endoplasmic reticulum stress in acrolein-induced endothelial activation.
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DOI：
10.1016/j.taap.2008.09.019
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发表时间：
2009-01-01
影响因子：
3.8
通讯作者：
Bhatnagar A
中科院分区：
文献类型：
--
作者：
Haberzettl P;Vladykovskaya E;Srivastava S;Bhatnagar A
丙烯醛是一种普遍存在的环境污染物，是脂质过氧化的内源性产物。它也在几种药物和氨基酸的代谢过程中产生。在这项研究中，我们研究了丙烯醛对内皮细胞的影响。用2至10 μM丙烯醛处理人脐静脉内皮细胞（HUVECs），在暴露10至30分钟内导致eIF-2α磷酸化水平增加。随后是XBP-1 mRNA的选择性剪接和内质网（ER）伴侣基因Grp 78和Herp表达的增加。在处理的2-4小时内，丙烯醛还增加了转录因子ATF 3、AFT 4和CHOP的丰度和核转运。丙烯醛诱导的ATF 3增加通过用化学伴侣-苯基丁酸（PBA）处理细胞来防止。丙烯醛处理增加ERK 1/2、p38和JNK的磷酸化。JNK磷酸化的增加被PBA阻止。丙烯醛处理导致转录因子NF-κB的活化和核转位，以及TNF-α、IL-6和IL-8 mRNA的增加，但不导致MCP-1 mRNA的增加。PBA处理的细胞中未观察到细胞因子基因合成增加和NF-κB活化。这些结果表明，暴露于丙烯醛诱导ER应激和触发未折叠的蛋白质反应，NF-κB激活和刺激细胞因子的产生，丙烯醛可以部分归因于ER应激。蛋白质折叠的化学分子伴侣可用于治疗与过量丙烯醛暴露或产生相关的毒理学和病理学状态。
Acrolein is a ubiquitous environmental pollutant and an endogenous product of lipid peroxidation. It is also generated during the metabolism of several drugs and amino acids. In this study, we examined the effects of acrolein on endothelial cells. Treatment of human umbilical vein endothelial cells (HUVECs) with 2 to 10 μM acrolein led to an increase in the phosphorylation of eIF-2α within 10 to 30 min of exposure. This was followed by alternate splicing of XBP-1 mRNA and an increase in the expression of the endoplasmic reticulum (ER) chaperone genes Grp78 and Herp. Within 2–4 h of treatment, acrolein also increased the abundance and the nuclear transport of the transcription factors ATF3, AFT4, and CHOP. Acrolein-induced increase in ATF3 was prevented by treating the cells with the chemical chaperone – phenylbutryic acid (PBA). Treatment with acrolein increased phosphorylation of ERK1/2, p38, and JNK. The increase in JNK phosphorylation was prevented by PBA. Acrolein treatment led to the activation and nuclear translocation of the transcription factor NF-κB and an increase in TNF-α, IL-6 and IL-8, but not MCP-1, mRNA. Increased synthesis of cytokine genes and NF-κB activation were not observed in cells treated with PBA. These findings suggest that exposure to acrolein induces ER stress and triggers the unfolded protein response and that NF-κB activation and stimulation of cytokine production by acrolein could be attributed, in part, to ER stress. Chemical chaperones of protein-folding may be useful in treating toxicological and pathological states associated with excessive acrolein exposure or production.
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影响因子：
4.8
作者：
Lambert, Cherie;Li, Jimei;Freed, Brian M.
通讯作者：
Freed, Brian M.
影响因子：
20.1
作者：
BHATNAGAR, A
通讯作者：
BHATNAGAR, A
影响因子：
4.8
作者：
Horton, ND;Biswal, SS;Kehrer, JP
通讯作者：
Kehrer, JP
影响因子：
2
作者：
Daimon, M;Sugiyama, K;Kato, T
通讯作者：
Kato, T
影响因子：
3.8
作者：
Hyvelin, JM;Roux, E;Marthan, R
通讯作者：
Marthan, R