Probucol aggravates long QT syndrome associated with a novel missense mutation M124T in the N-terminus of HERG

Hayashi, Kenshi; Shimizu, Masami; Ino, Hidekazu; Yamaguchi, Masato; Terai, Hidenobu; Hoshi, Naoto; Higashida, Haruhiro; Terashima, Nariaki; Uno, Yusuke; Kanaya, Honin; Mabuchi, Hiroshi

doi:10.1042/cs20030351

Cited by 40 publications

(32 citation statements)

References 31 publications

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“…Probucol is a cholesterol-lowering drug that causes long QT syndrome and torsades de pointes arrhythmia in patients (Hayashi et al, 2004). We demonstrated previously that probucol reduces the expression levels of the mature form of ERG (I Kr protein) in cultured cardiomyocytes and of 155-kDa hERG channels stably expressed in HEK 293 cells (Guo et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Involvement of Caveolin in Probucol-Induced Reduction in hERG Plasma-Membrane Expression

Guo¹,

Li²,

Shallow³

et al. 2011

Mol Pharmacol

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The human ether-à -go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier K ϩ current (I Kr ) important for cardiac repolarization. Dysfunction of the hERG channel causes long QT syndrome (LQTS). Although diverse compounds reduce the hERG current (I hERG ) by blocking the channel, probucol, a cholesterol-lowering drug that causes LQTS, reduces I hERG by decreasing plasma-membrane hERG protein expression. Here, we investigated the mechanisms of probucol effects on hERG expression levels. Our data demonstrate that probucol accelerated the degradation of mature hERG channels, which associated with caveolin-1 (Cav1) in hERG-expressing HEK cells. In human embryonic kidney (HEK) cells without hERG expression, probucol promoted endogenous Cav1 degradation. In hERG-expressing HEK cells, overexpression of Cav1 enhanced, whereas knockdown of Cav1 impeded, probucol-induced reduction of mature hERG channels. Thus, probucol reduces hERG expression through accelerating Cav1 turnover. The effects of probucol on Cav1 and hERG result from probucol's cholesterol-disrupting action, because low-density lipoprotein (LDL), a potent cholesterol carrier, effectively prevented probucol-induced reduction of I hERG in hERG-expressing HEK cells and of I Kr in neonatal rat cardiomyocytes. Our data provide evidence that targeting hERG-interacting protein caveolin represents a novel mechanism for drugs to decrease hERG expression and cause LQTS.

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Section: Discussionmentioning

confidence: 99%

Involvement of Caveolin in Probucol-Induced Reduction in hERG Plasma-Membrane Expression

Guo¹,

Li²,

Shallow³

et al. 2011

Mol Pharmacol

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“…17 The green circles in Figure 1C indicate the location of 8 mutations previously reported in dLQTS. [5][6][7][8][9][10] …”

mentioning

confidence: 99%

Latent Genetic Backgrounds and Molecular Pathogenesis in Drug-Induced Long-QT Syndrome

Itoh

Sakaguchi

Ding

et al. 2009

Circ: Arrhythmia and Electrophysiology

105

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Background-Drugs with I Kr -blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown. Methods and Results-Genetic testing was carried out for long-QT syndrome-related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, Pϭ0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, PϽ0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS. Conclusions-dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When I Kr -blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome. (Circ Arrhythmia Electrophysiol. 2009;2:511-523.)Key Words: long-QT syndrome Ⅲ secondary Ⅲ drug Ⅲ electrophysiology Ⅲ ion channel C ongenital long-QT syndrome (cLQTS) is characterized by abnormally prolonged ventricular repolarization and familial inheritance, leading to polymorphic ventricular tachycardia (torsades de pointes [TdP]), causing sudden cardiac death. 1,2 In contrast, secondary long-QT syndrome can be induced by a variety of commercially available drugs, including antiarrhythmic drugs, antihistamines, antibiotics, Clinical Perspective on p 523and major tranquilizers. 3 In patients with drug-induced long-QT syndrome (dLQTS), after a washout period of the culprit drugs, the QT interval usually returns to within normal range. Genetic factors may underlie the susceptibility to drug-induced serious adverse reactions such as a long QT Received February 29, 2008; accepted July 6, 2009. (eg, drugs, hypokalemia, or bradycardia). Among the subjects, 20 probands had drug-induced cardiac events (10.2% of long-QT syndrome probands). Their clinical information was collected, including family history of sudden death age 30 years or younger and long-QT syndrome members, previ...

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“…The similarity in mechanism is also increasingly evident between Class Ia anti-arrhythmic drugs and the hypoglycemic function of SUs and glinides (Kakei et al, 1993;Hayashi et al, 2004). SUs and www.intechopen.com glinides can potentially induce QT prolongation when they affect the heart's ATPdependent K + channels.…”

Section: Sulfonylureas (Sus) and Glinides As Oral Anti-diabetic Drugsmentioning

confidence: 99%

“…A study has been done on probucol induced QT prolongation as a result of a change in catecholamine sensitivity, as well as K + current inhibition (Hayashi et al, 2004). Further study and consideration is needed.…”

Section: Othersmentioning

confidence: 99%

Medicines and QT Prolongation

Kato¹,

Ijiri²,

Tanaka³

2012

Advances in Electrocardiograms - Methods and Analysis

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Probucol aggravates long QT syndrome associated with a novel missense mutation M124T in the N-terminus of HERG

Cited by 40 publications

References 31 publications

Involvement of Caveolin in Probucol-Induced Reduction in hERG Plasma-Membrane Expression

Involvement of Caveolin in Probucol-Induced Reduction in hERG Plasma-Membrane Expression

Latent Genetic Backgrounds and Molecular Pathogenesis in Drug-Induced Long-QT Syndrome

Medicines and QT Prolongation

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