Activation of volume-sensitive outwardly rectifying chloride channel by ROS contributes to ER stress and cardiac contractile dysfunction: involvement of CHOP through Wnt

Abstract

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.

Ophiopogonin D maintains Ca2+ homeostasis in rat cardiomyocytes in vitro by upregulating CYP2J3/EETs and suppressing ER stress

“…The CHOP, JNK and caspase-12 ER stress pathways were significantly induced in the Ang II-treated cardiomyocytes. Although the ER stress-induced apoptotic pathway has not been fully characterized, three hallmarks of the process have been identified, including the upregulation of pro-apoptotic transcription factor CHOP, JNK [12,44,45] and the activation of the ER-localized caspase-12 [45,46] . After triggering ER stress, GRP78 expression is also dramatically elevated, which may be a biomarker of ER stress.…”

“…Impaired intracellular Ca 2+ homeostasis is a documented and common feature of heart disease, which is a consequence of the dysregulation of Ca 2+ -cycling proteins [43,[2][3] . Modifications in Ca 2+ homeostasis are also a major mechanism that produces abnormal ER stress and apoptosis [44] ; uncontrolled increases in the Ca 2+ concentrations and Ca 2+ depletion are known to trigger apoptosis by directly activating the ER-resident proteins CHOP, p-JNK and caspase-12 [12,[44][45][46] . Additionally, Ang II can directly cause contractile dysfunction and heart [47,48] .…”

Crocin protects PC12 cells against MPP+-induced injury through inhibition of mitochondrial dysfunction and ER stress

“…Wnt is an essential cell protective mediator under cellular stress conditions (Logan and Nusse, 2004;Marchetti et al, 2013), and increased Wnt signal induced by dishevelled-1 knockdown was shown to attenuate cyclosporine A-induced apoptosis in H9C2 cardiomyoblast cells (Zhu et al, 2013). More recently, Wnt was shown to inhibit tunicamycin-induced ER stress in cardiomycytes (Shen et al, 2014). Our data showed that MPP + significantly decreased the nuclear localization of β-catenin and Topflash activity, which was shown to reversely correlate with CHOP.…”

Activation of volume-sensitive Cl− channel mediates autophagy-related cell death in myocardial ischaemia/reperfusion injury

“…VSOR chlorine currents are sensitive to chlorine channel blockers. Our previous study revealed that DCPIB could suppress cardiomyocyte apoptosis through inhibition of VSOR Cl − channel-activated [33, 34]. However, no evidence is currently available regards to the role of VSOR Cl − channel in autophagy-related cell death regulation, and whether autophagy participates in regulation of cell volume has not been elucidated.…”