Activation of volume-sensitive outwardly rectifying chloride channel by ROS contributes to ER stress and cardiac contractile dysfunction: involvement of CHOP through Wnt.
Activation of volume-sensitive outwardly rectifying chloride channel by ROS contributes to ER stress and cardiac contractile dysfunction: involvement of CHOP through Wnt.
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ROS 激活容量敏感的外向整流氯离子通道导致 ER 应激和心肌收缩功能障碍：CHOP 通过 Wnt 参与
DOI：
10.1038/cddis.2014.479
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发表时间：
2014-11-20
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
内质网应激在严酷的条件下发生，与心肌细胞的凋亡和心脏收缩功能障碍(CCD)密切相关。然而，介导心脏内质网应激和随后的细胞死亡的分子机制仍有待完全破译，这有望为这些疾病提供新的治疗靶点。在这里，我们建立了衣霉素诱导的心肌细胞内质网应激模型，该模型有效地模拟了病理刺激触发电荷耦合器件。衣霉素激活容量敏感的外向整流Cl-−电流。非选择性氯−通道阻断剂4，4‘-二异硫杂二苯乙烯-2，2’-二磺酸(DIDS)和选择性氯离子通道阻滞剂4-(2-丁基-6，7-二氯-2-环戊基-吲哚-1-on-5-基)氧丁酸(DCPIB)阻断容量敏感的外向整流(VSOR)氯−通道，改善心肌收缩功能，通过抑制经典的GRP78/eIF2−/α/ATF4和XBP1途径抑制内质网应激，促进心肌细胞存活。衣霉素处理的心肌细胞的VSOR激活归因于细胞内活性氧(ROS)水平的增加。我们的研究证实了ROS/VSOR通过CHOP-WNT途径在介导内质网应激和心肌细胞功能损害中的关键作用，并提示VSORCL−通道阻滞剂对内质网应激相关心脏异常的治疗价值。
Endoplasmic reticulum (ER) stress occurring in stringent conditions is critically involved in cardiomyocytes apoptosis and cardiac contractile dysfunction (CCD). However, the molecular machinery that mediates cardiac ER stress and subsequent cell death remains to be fully deciphered, which will hopefully provide novel therapeutic targets for these disorders. Here, we establish tunicamycin-induced model of cardiomyocyte ER stress, which effectively mimicks pathological stimuli to trigger CCD. Tunicamycin activates volume-sensitive outward rectifying Cl− currents. Blockade of the volume-sensitive outwardly rectifying (VSOR) Cl− channel by 4, 4'-diisothiocya-natostilbene-2, 2'-disulfonic acid (DIDS), a non-selective Cl− channel blocker, and 4-(2-butyl-6, 7-dichlor-2-cyclopentyl-indan-1-on-5-yl) oxybutyric acid (DCPIB), a selective VSOR Cl− channel blocker, improves cardiac contractility, which correlates with suppressed ER stress through inhibiting the canonical GRP78/eIF2α/ATF4 and XBP1 pathways, and promotes survival of cardiomyocytes by inverting tunicamycin-induced decrease of Wnt through the CHOP pathway. VSOR activation of tunicamycin-treated cardiomyocytes is attributed to increased intracellular levels of reactive oxygen species (ROS). Our study demonstrates a pivotal role of ROS/VSOR in mediating ER stress and functional impairment of cardiomyocytes via the CHOP-Wnt pathway, and suggests the therapeutic values of VSOR Cl− channel blockers against ER stress-associated cardiac anomalies.
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DOI：
10.1085/jgp.200409040
发表时间：
2004-09
期刊：
The Journal of general physiology
影响因子：
--
作者：
Browe DM;Baumgarten CM
通讯作者：
Baumgarten CM
影响因子：
82.9
作者：
Erbay, Ebru;Babaev, Vladimir R.;Mayers, Jared R.;Makowski, Liza;Charles, Khanichi N.;Snitow, Melinda E.;Fazio, Sergio;Wiest, Michelle M.;Watkins, Steven M.;Linton, MacRae F.;Hotamisligil, Goekhan S.
通讯作者：
Hotamisligil, Goekhan S.
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
--
作者：
Liu, An-Heng;Cao, Ya-Nan;Wang, Xiao-Ming
通讯作者：
Wang, Xiao-Ming
影响因子：
10.8
作者：
George, Isaac;Sabbah, Hani N.;Wang, Jie
通讯作者：
Wang, Jie