Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

General Research Article

Probucol-induced hERG Channel Reduction can be Rescued by Matrine and Oxymatrine in vitro

Author(s): Yuan-Qi Shi, Pan Fan, Guo-Cui Zhang, Yu-Hao Zhang, Ming-Zhu Li, Fang Wang and Bao-Xin Li*

Volume 25, Issue 43, 2019

Page: [4606 - 4612] Pages: 7

DOI: 10.2174/1381612825666191026170033

open access plus


Background: The human ether-a-go-go-related gene (hERG) potassium channel is the rapidly activating component of cardiac delayed rectifier potassium current (IKr), which is a crucial determinant of cardiac repolarization. The reduction of hERG current is commonly believed to cause Long QT Syndrome (LQTs). Probucol, a cholesterol-lowering drug, induces LQTs by inhibiting the expression of the hERG channel. Unfortunately, there is currently no effective therapeutic method to rescue probucol-induced LQTs.

Methods: Patch-clamp recording techniques were used to detect the action potential duration (APD) and current of hERG. Western blot was performed to measure the expression levels of proteins.

Results: In this study, we demonstrated that 1 μM matrine and oxymatrine could rescue the hERG current and hERG surface expression inhibited by probucol. In addition, matrine and oxymatrine significantly shortened the prolonged action potential duration induced by probucol in neonatal cardiac myocytes. We proposed a novel mechanism underlying the probucol induced decrease in the expression of transcription factor Specificity protein 1 (Sp1), which is an established transactivator of the hERG gene. We also demonstrated that matrine and oxymatrine were able to upregulate Sp1 expression which may be one of the possible mechanisms by which matrine and oxymatrine rescued probucol-induced hERG channel deficiency.

Conclusion: Our current results demonstrate that matrine and oxymatrine could rescue probucol-induced hERG deficiency in vitro, which may lead to potentially effective therapeutic drugs for treating acquired LQT2 by probucol in the future.

Keywords: Probucol, Human ether-a-go-go-related gene, matrine, oxymatrine, specificity protein 1, cardiac repolarization.

Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 1995; 81(2): 299-307.
[] [PMID: 7736582]
Keating MT, Sanguinetti MC. Molecular and cellular mechanisms of cardiac arrhythmias. Cell 2001; 104(4): 569-80.
[] [PMID: 11239413]
Patel C, Yan GX, Antzelevitch C. Short QT syndrome: from bench to bedside. Circ Arrhythm Electrophysiol 2010; 3(4): 401-8.
[] [PMID: 20716721]
Raschi E, Vasina V, Poluzzi E, De Ponti F. The hERG K+ channel: Target and antitarget strategies in drug development. Pharmacol Res 2008; 57(3): 181-95.
[] [PMID: 18329284]
Dennis A, Wang L, Wan X, Ficker E. hERG channel trafficking: novel targets in drug-induced long QT syndrome. Biochem Soc Trans 2007; 35(Pt. 5): 1060-3.
[] [PMID: 17956279]
van der Heyden MA, Smits ME, Vos MA. Drugs and trafficking of ion channels: a new pro-arrhythmic threat on the horizon? Br J Pharmacol 2008; 153(3): 406-9.
[] [PMID: 18059314]
Tamura M, Ueki Y, Ohtsuka E, et al. Probucol-induced QT prolongation and syncope. Jpn Circ J 1994; 58(5): 374-7.
[] [PMID: 8022053]
Guo J, Massaeli H, Li W, et al. Identification of IKr and its trafficking disruption induced by probucol in cultured neonatal rat cardiomyocytes. J Pharmacol Exp Ther 2007; 321(3): 911-20.
[] [PMID: 17377062]
Guo J, Li X, Shallow H, et al. Involvement of caveolin in probucol-induced reduction in hERG plasma-membrane expression. Mol Pharmacol 2011; 79(5): 806-13.
[] [PMID: 21278233]
Hong-Li S, Lei L, Lei S, et al. Cardioprotective effects and underlying mechanisms of oxymatrine against Ischemic myocardial injuries of rats. Phytother Res 2008; 22(7): 985-9.
[] [PMID: 18389484]
Zhang L, Wang T, Wen X, et al. Effect of matrine on HeLa cell adhesion and migration. Eur J Pharmacol 2007; 563(1-3): 69-76.
[] [PMID: 17343841]
Ho JW, Ngan Hon PL, Chim WO. Effects of oxymatrine from Ku Shen on cancer cells. Anticancer Agents Med Chem 2009; 9(8): 823-6.
[] [PMID: 19538168]
Liu J, Zhu M, Shi R, Yang M. Radix Sophorae flavescentis for chronic hepatitis B: a systematic review of randomized trials. Am J Chin Med 2003; 31(3): 337-54.
[] [PMID: 12943166]
Hu MQ, Dong ZX, Zhao WX, et al. The novel mechanism of oxymatrine affecting HERG currents at different temperatures. Cell Physiol Biochem 2010; 26(4-5): 513-22.
[] [PMID: 21063089]
Zhang Y, Du J, Zhang Y, et al. [Effects of matrine, oxymatrine and resveratrol on HERG channel expression]. Yao Xue Xue Bao 2007; 42(2): 139-44.
[PMID: 17518040]
Zhang Y, Dong Z, Jin L, et al. Arsenic trioxide-induced hERG K(+) channel deficiency can be rescued by matrine and oxymatrine through up-regulating transcription factor Sp1 expression. Biochem Pharmacol 2013; 85(1): 59-68.
[] [PMID: 23103450]
Du X, Lu D, Daharsh ED, Yao A, Dewoody R, Yao JA. Dimethyl sulfoxide effects on hERG channels expressed in HEK293 cells. J Pharmacol Toxicol Methods 2006; 54(2): 164-72.
[] [PMID: 16782359]
Gu DF, Li XL, Qi ZP, et al. Blockade of HERG K+ channel by isoquinoline alkaloid neferine in the stable transfected HEK293 cells. Naunyn Schmiedebergs Arch Pharmacol 2009; 380(2): 143-51.
[] [PMID: 19424681]
Hayashi K, Shimizu M, Ino H, et al. Probucol aggravates long QT syndrome associated with a novel missense mutation M124T in the N-terminus of HERG. Clin Sci (Lond) 2004; 107(2): 175-82.
[] [PMID: 15043509]
Heeg JF, Tachizawa H. Plasma levels of probucol in man after single and repeated oral doses (author’s transl). Nouv Presse Med 1980; 9(40): 2990-4.
[PMID: 7443437]
Ficker E, Dennis AT, Wang L, Brown AM. Role of the cytosolic chaperones Hsp70 and Hsp90 in maturation of the cardiac potassium channel HERG. Circ Res 2003; 92(12): e87-e100.
[] [PMID: 12775586]
Delisle BP, Anson BD, Rajamani S, January CT. Biology of cardiac arrhythmias: Ion channel protein trafficking. Circ Res 2004; 94(11): 1418-28.
[] [PMID: 15192037]
Dennis AT, Wang L, Wan H, Nassal D, Deschenes I, Ficker E. Molecular determinants of pentamidine-induced hERG trafficking inhibition. Mol Pharmacol 2012; 81(2): 198-209.
[] [PMID: 22046004]
Lai JP, He XW, Jiang Y, Chen F. Preparative separation and determination of matrine from the Chinese medicinal plant Sophora flavescens Ait by molecularly imprinted solid-phase extraction. Anal Bioanal Chem 2003; 375(2): 264-9.
[] [PMID: 12560971]
Kang JE, Kim MH, Lee JA, et al. Histone deacetylase-1 represses transcription by interacting with zinc-fingers and interfering with the DNA binding activity of Sp1. Cell Physiol Biochem 2005; 16(1-3): 23-30.
[] [PMID: 16121030]
Mucha M, Ooi L, Linley JE, et al. Transcriptional control of KCNQ channel genes and the regulation of neuronal excitability. J Neurosci 2010; 30(40): 13235-45.
[] [PMID: 20926649]
Li Q, Zhang Y, Sheng Y, et al. Large T-antigen up-regulates Kv4.3 K+ channels through Sp1, and Kv4.3 K+ channels contribute to cell apoptosis and necrosis through activation of calcium/calmodulin-dependent protein kinase II. Biochem J 2012; 441(3): 859-67.
[] [PMID: 22023388]
Vij N, Zeitlin PL. Regulation of the ClC-2 lung epithelial chloride channel by glycosylation of SP1. Am J Respir Cell Mol Biol 2006; 34(6): 754-9.
[] [PMID: 16456185]
Simard JM, Chen M, Tarasov KV, et al. Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke. Nat Med 2006; 12(4): 433-40.
[] [PMID: 16550187]

© 2022 Bentham Science Publishers | Privacy Policy