title: Arsenic trioxide-induced hERG K(+) channel deficiency can be rescued by matrine and oxymatrine through up-regulating transcription factor Sp1 expression.
abstract: The human ether-a-go-go-related gene (hERG) encodes the rapidly activating, delayed rectifier potassium channel (IKr) important for cardiac repolarization. Dysfunction of the hERG channel can cause Long QT Syndrome (LQTS). A wide variety of structurally diverse therapeutic compounds reduce the hERG current by acute direct inhibition of the hERG current or/and selective disruption of hERG protein expression. Arsenic trioxide (As(2)O(3)), which is used to treat acute promyelocytic leukemia, can cause LQTS type 2 (LQT2) by reducing the hERG current through the diversion of hERG trafficking to the cytoplasmic membrane. This cardiotoxicity limits its clinical applications. Our aim was to develop cardioprotective agents to decrease As(2)O(3)-induced cardiotoxicity. We reported that superfusion of hERG-expressing HEK293 (hERG-HEK) cells with matrine (1, 10 μM) increased the hERG current by promoting hERG channel activation. Long-term treatment with 1 μM matrine or oxymatrine increased expression of the hERG protein and rescued the hERG surface expression disrupted by As(2)O(3). In addition, Matrine and oxymatrine significantly shortened action potential duration prolonged by As(2)O(3) in guinea pig ventricular myocytes. These results were ascribed to the up-regulation of hERG at both mRNA and protein levels via an increase in the expression of transcription factor Sp1, an established transactivator of the hERG gene. Therefore, matrine and oxymatrine may have the potential to cure LQT2 as a potassium channel activator by promoting hERG channel activation and increasing hERG channel expression.
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, 150086, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zengxiang
authors.initials: Z
authors.lastname: Dong
authors.forename: Liyan
authors.initials: L
authors.lastname: Jin
authors.forename: Kaiping
authors.initials: K
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Jia
authors.initials: J
authors.lastname: Fu
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.forename: Mingming
authors.initials: M
authors.lastname: Sun
authors.forename: Baofeng
authors.initials: B
authors.lastname: Yang
authors.forename: Baoxin
authors.initials: B
authors.lastname: Li
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000502:physiology*; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D010087:Oxides / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011401:Promoter Regions, Genetic; D011807:Quinolizines / Q000494:pharmacology*; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D015854:Up-Regulation; D000093842:Matrines
chemical_list: D000470:Alkaloids; D001152:Arsenicals; D002317:Cardiovascular Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010087:Oxides; D011807:Quinolizines; D016329:Sp1 Transcription Factor; C037573:oxymatrine; D000077237:Arsenic Trioxide; D000093842:Matrines