title: 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.
authors.affiliation: 1] Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, China [2] Department of Cardiology, Hainan Branch of PLA General Hospital, Sanya, China.
authors.forename: M
authors.initials: M
authors.lastname: Shen
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: G
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: L
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: X
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: L
authors.initials: L
authors.lastname: Jia
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D003517:Cyclopentanes / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D007189:Indans / Q000494:pharmacology; D051379:Mice; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology*; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism; D000071717:X-Box Binding Protein 1
chemical_list: C443139:4-(2-butyl-6,7-dichlor-2-cyclopentyl-indan-1-one-5-yl)oxybutyric acid; C497110:Atf4 protein, rat; D018118:Chloride Channels; D003517:Cyclopentanes; D004268:DNA-Binding Proteins; C497251:Ddit3 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; C051684:GRP78 protein, rat; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D007189:Indans; D017382:Reactive Oxygen Species; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D051153:Wnt Proteins; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C000605545:Xbp1 protein, rat; D014415:Tunicamycin; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid