Arsenic trioxide-induced hERG K+ channel deficiency can be rescued by matrine and oxymatrine through up-regulating transcription factor Sp1 expression

Zhang, Ying; Dong, Zengxiang; Jin, Liyan; Zhang, Kaiping; Zhao, Xin; Fu, Jia; Gong, Yan; Sun, Mingming; Yang, Baofeng; Li, Baoxin

doi:10.1016/j.bcp.2012.09.002

Cited by 41 publications

(45 citation statements)

References 37 publications

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“…Current and action potential recordings were performed as described previously [10]. Briefly, after incubation of BBR for 24h, HEK293/hERG cells were trypsinized, centrifuged and stored at 4°C in bath solution for 1h to stabalize seperated-single cells.…”

Section: Methodsmentioning

confidence: 99%

Berberine Induces hERG Channel Deficiency through Trafficking Inhibition

Zhang

Zhi

Huang

et al. 2014

Cell Physiol Biochem

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Aims: The human ether-a-go-go-related gene (hERG) encodes the α subunit of the IKr, which plays an essential role in repolarization of action potentials. hERG channels are targeted by various pro-arrhythmic drugs. Berberine (BBR) was previously found to acutely inhibit hERG currents and prolong action potential duration. The present study aimed to determine long-term effects of BBR on the expression of 135kDa/155kDa hERG and the mechanism. Methods and Results: hERG expression was assessed by western blot. Mature hERG (155 kDa) was reduced, whereas ER-located hERG (135 kDa) was increased by BBR. This indicated that hERG was restricted to the ER and that BBR disrupted channel trafficking. To determine the mechanism of trafficking inhibition, we performed western blot and immunoprecipitation to test folding of hERG by assessing interaction between hERG and Hsp90/Hsp70. Both the expression of Hsp90 and its interaction with hERG were strongly decreased by BBR. These data suggest that BBR reduces channel folding to induce trafficking inhibition. Western blot and confocal imaging were used to further detect whether the unfolded protein response (UPR) was activated. Active ATF6, a marker of the UPR, was activated by BBR. Calnexin and calreticulin, chaperones that are activated by ATF6 to assist channel folding, were also elevated and increasingly colocalized with hERG. These data also demonstrate that the UPR was activated. Immunoprecipitation and western blot assays were performed after BBR treatment to examine ubiquitination and degradation, common endpoints of the UPR. We found that the ER-restricted hERG was ubiquitinized and degraded in the lysosomes and proteasomes. Conclusion: Our study demonstrates that BBR induces hERG channel deficiency by inhibiting channel trafficking after incubation for 24h. Trafficking inhibition activated the UPR, and the ER-restricted hERG was ubiquitinized and degraded in lysosomes and proteasomes.

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Section: Methodsmentioning

confidence: 99%

Berberine Induces hERG Channel Deficiency through Trafficking Inhibition

Zhang

Zhi

Huang

et al. 2014

Cell Physiol Biochem

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“…55 Furthermore, OMT was shown to induce the Sp1 transcription factor expression in human embryonic kidney 293 cells. 56 Taken together, the OMT beneficial effects on cardiac tissue seem to be related to the activation of SERCA2a expression through tumor necrosis factor-α inhibition or Sp1 increased expression. These findings encourage further investigation about OMT and other natural products that could serve as SERCA2a direct or indirect activators.…”

mentioning

confidence: 94%

SERCA2a: its role in the development of heart failure and as a potential therapeutic target

Fragoso-Medina¹,

Zarain‐Herzberg²

2014

RRCC

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Abstract:The complexity of heart physiology has delayed the implementation of efficient, feasible, and safe therapies to fight against heart diseases for many years. As knowledge of the precise mechanisms governing cardiac hypertrophy and heart failure development increases, the availability of new therapeutic alternatives also grows. Since the cardiomyocyte physiology deeply depends on the correct calcium handling, many efforts to describe accurately the excitation-contraction coupling process in the heart and the proteins involved have been made. Among the proteins participating in calcium handling, sarco/endoplasmic reticulum Ca 2+ adenosine triphosphatase-2a (SERCA2a), whose expression and function is decreased in heart failure, stands out because of its critical role regulating Ca 2+ concentration in the cardiomyocyte. The importance of SERCA2a has been reflected in numerous studies aimed to describe its expression and function. Recently, gene therapy to deliver SERCA2a has shown promising results in human clinical trials. This paper reviews the current literature knowledge exploring diverse approaches to rescue SERCA2a expression in heart failure. It also discusses some data suggesting other possible therapies that could improve SERCA2a expression and function in cardiac diseases.

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“…ICA-105574 can also disable hERG inactivation and shorten the QT interval in cardiomyocytes [18,84] . Moreover, matrine and oxymatrine can also rescue arsenic trioxide-induced hERG deficiency and APD prolongation [22] . ALLN successfully reduces spontaneous arrhythmogenic episodes and markedly reduces APD 70/90 of LQTS-specific cardiomyocytes derived from human-induced pluripotent stem cells [87] .…”

Section: Existing and Potential Rescue Strategiesmentioning

confidence: 99%

“…It has also been reported that an extensively expressed transcriptional factor, SP1, up-regulates hERG mRNA. Furthermore, drugs may also rescue arsenic trioxide-induced hERG deficiency through upregulation of SP1 [22] . Thus, NMD and SP1 might be good entry points through which interference of hERG dysfunction may occur.…”

Section: Transcription In Nucleusmentioning

confidence: 99%

“…(4) A-935142 and mallotoxin both regulate the hERG channel by changing multiple kinetics [20,83] . (5) Matrine and oxymatrine influence the hERG channel by up-regulating transcription instead of changing kinetics [22,85] . (6) Carbachol increases Nedd4-2 phosphorylation, slows down channel degradation and thus increases hERG channel expression [86] .…”

Section: Existing and Potential Rescue Strategiesmentioning

confidence: 99%

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Translational toxicology and rescue strategies of the hERG channel dysfunction: biochemical and molecular mechanistic aspects

Zhang

Yang

2014

Acta Pharmacol Sin

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The human ether-à-go-go related gene (hERG) potassium channel is an obligatory anti-target for drug development on account of its essential role in cardiac repolarization and its close association with arrhythmia. Diverse drugs have been removed from the market owing to their inhibitory activity on the hERG channel and their contribution to acquired long QT syndrome (LQTS). Moreover, mutations that cause hERG channel dysfunction may induce congenital LQTS. Recently, an increasing number of biochemical and molecular mechanisms underlying hERG-associated LQTS have been reported. In fact, numerous potential biochemical and molecular rescue strategies are hidden within the biogenesis and regulating network. So far, rescue strategies of hERG channel dysfunction and LQTS mainly include activators, blockers, and molecules that interfere with specific links and other mechanisms. The aim of this review is to discuss the rescue strategies based on hERG channel toxicology from the biochemical and molecular perspectives.

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Arsenic trioxide-induced hERG K+ channel deficiency can be rescued by matrine and oxymatrine through up-regulating transcription factor Sp1 expression

Cited by 41 publications

References 37 publications

Berberine Induces hERG Channel Deficiency through Trafficking Inhibition

Berberine Induces hERG Channel Deficiency through Trafficking Inhibition

SERCA2a: its role in the development of heart failure and as a potential therapeutic target

Translational toxicology and rescue strategies of the hERG channel dysfunction: biochemical and molecular mechanistic aspects

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