title: The rescuable function and mechanism of resveratrol on As₂O₃-induced hERG K⁺ channel deficiency.
abstract: Arsenic trioxide (As2O3) is used to treat acute promyelocytic leukemia. However, the cardiotoxicity of long QT syndrome restricts its clinical application. Previous studies showed that As2O3 can damage the human ether-a-go-go-related gene (hERG) current via disturbing its trafficking to cellular membrane. This study aimed to investigate whether the As2O3-insulted hERG channel can be rescued by resveratrol, a recognized cardioprotective agent. The whole-cell patch clamp technique was used to record the hERG current and action potential duration. Co-immunoprecipitation and Western blot assay were applied to determine the function of hERG-Hsp70/Hsp90 chaperone complexes and the expression alteration of protein-folding-related proteins, respectively. Compared with treatment of As2O3 alone, co-treatment with resveratrol successfully restored the current and surface expression of hERG and obviously shortened action potential duration in guinea pig ventricular myocytes. Further experiments demonstrate that resveratrol relieved As2O3-caused endoplasmic reticulum (ER) stress by restoring the function of hERG-Hsp70/Hsp90 chaperone complexes and downregulating the protein expression of ER chaperone proteins (calnexin and calreticulin) and activating transcription factor 6. In conclusion, resveratrol was able to rescue the trafficking deficiency and relieve the ER stress (ERS). Our findings suggest that resveratrol has a potential effect to alleviate the adverse effect of As2O3 on cardiotoxicity.
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, 150086, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Kai-Ping
authors.initials: KP
authors.lastname: Zhang
authors.forename: Ting
authors.initials: T
authors.lastname: Huang
authors.forename: Cai-Chuan
authors.initials: CC
authors.lastname: Yan
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Liu
authors.forename: Qi-Lei
authors.initials: QL
authors.lastname: Zhu
authors.forename: Feng-Feng
authors.initials: FF
authors.lastname: Guo
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Bao-Xin
authors.initials: BX
authors.lastname: Li
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D000077237:Arsenic Trioxide; D001152:Arsenicals; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology; D066126:Cardiotoxicity / Q000209:etiology / Q000517:prevention & control*; D015536:Down-Regulation / Q000187:drug effects; D000072237:ERG1 Potassium Channel; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D051638:Ether-A-Go-Go Potassium Channels / Q000172:deficiency; D006168:Guinea Pigs; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010087:Oxides / Q000633:toxicity*; D018408:Patch-Clamp Techniques; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D002316:Cardiotonic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; C000606913:KCNH2 protein, human; D010087:Oxides; D013267:Stilbenes; D000077185:Resveratrol; D000077237:Arsenic Trioxide
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