title: Volume-sensitive outwardly rectifying chloride channel blockers protect against high glucose-induced apoptosis of cardiomyocytes via autophagy activation.
abstract: Hyperglycemia is a well-characterized contributing factor for cardiac dysfunction and heart failure among diabetic patients. Apoptosis of cardiomyocytes plays a major role during the onset and pathogenesis of diabetic cardiomyopathy (DCM). Nonetheless, the molecular machinery underlying hyperglycemia-induced cardiac damage and cell death remains elusive. In the present study, we found that chloride channel blockers, 4,4'-diisothiocya-natostilbene-2,2'- disulfonic acid (DIDS) and 4-(2-butyl-6,7-dichlor-2-cyclopentyl-indan-1-on-5-yl) oxybutyric acid (DCPIB), inhibited high glucose-activated volume-sensitive outwardly rectifying (VSOR) Cl-channel and improved the viability of cardiomyocytes. High glucose induced cardiomyocyte apoptosis by suppressing the autophagic stress, which can be reversed via blockade of VSOR Cl-channel. VSOR activation in high glucose-treated cardiomyocytes was attributed to increased intracellular levels of reactive oxygen species (ROS). Taken together, our study unraveled a role of VSOR chloride currents in impaired autophagy and increased apoptosis of high glucose-exposed cardiomyocyte, and has implications for a therapeutic potential of VSOR chloride channel blockers in DCM.
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.|Department of Cardiology, Hainan Branch of PLA General Hospital, Sanya 572031, China.
authors.forename: Mingzhi
authors.initials: M
authors.lastname: Shen
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xiaowang
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Lintao
authors.initials: L
authors.lastname: Jia
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003517:Cyclopentanes / Q000494:pharmacology*; D015870:Gene Expression; D005947:Glucose / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007189:Indans / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D018118:Chloride Channels; D003517:Cyclopentanes; D005947:Glucose; D007189:Indans; D049990:Membrane Transport Modulators; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; C443139:4-(2-butyl-6,7-dichlor-2-cyclopentyl-indan-1-one-5-yl)oxybutyric acid; C526109:Anxa3 protein, rat