Ionic Mechanisms Underlying Abnormal QT Prolongation and the Associated Arrhythmias in Diabetic Rabbits: A Role of Rapid Delayed Rectifier K&lt;sup&gt;+&lt;/sup&gt; Current

Zhang, Yiqiang; Xiao, Jiening; Lin, Hao; Luo, Xiaobin; Wang, Huizhen; Bai, Yunlong; Wang, Jingxiong; Zhang, Haiqing; Yang, Baofeng; Wang, Zhiguo

doi:10.1159/000100642

Cited by 63 publications

(54 citation statements)

References 38 publications

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“…QT prolongation may result from attenuated repolarizing currents. Although the complement of K ϩ currents determining repolarization differs in humans and rats, the rapidly activating K ϩ current and slow component of delayed rectifier K ϩ current (I Ks ), which are prominent in human ventricle, are attenuated in a type 1 diabetic rabbit model (55). Interestingly, I Ks is attenuated by angiotensin II (3), emphasizing the possible parallels between activation of the RAS and electrophysiological derangements in rats and humans.…”

Section: Discussionmentioning

confidence: 99%

Sex-dependent impairment of cardiac action potential conduction in type 1 diabetic rats

Shimoni¹,

Emmett²,

Schmidt³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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The incidence of diabetes mellitus is increasing. Cardiac dysfunction often develops, resulting in diverse arrhythmias. These arise from ion channel remodeling or from altered speed and pattern of impulse propagation. Few studies have investigated impulse propagation in the diabetic heart. We previously showed a reduced conduction reserve in the diabetic heart, with associated changes in intercellular gap junctions. The present study investigated whether these effects are sex specific. Hearts from control and streptozotocin-diabetic male and female rats were used. Optical mapping was performed with the voltage-sensitive dye di-4-ANEPPS, using Langendorff-perfused hearts. Isolated ventricular cells and tissue sections were used for immunofluorescent labeling of the gap junction protein connexin43 (Cx43). The gap junction uncoupler heptanol (0.75 mM) or elevated K+ (9 mM, to reduce cell excitability) produced significantly greater slowing of propagation in diabetic males than females. In ovariectomized diabetic females, 9 mM K+ slowed conduction significantly more than in nonovariectomized females. The subcellular redistribution (lateralization) of the gap junction protein Cx43 was smaller in diabetic females. Pretreatment of diabetic males with the angiotensin-converting enzyme inhibitor quinapril reduced Cx43 lateralization and the effects of 9 mM K+ on propagation. In conclusion, the slowing of cardiac impulse propagation in type 1 diabetes is smaller in female rats, partly due to the presence of female sex hormones. This difference is (partly) mediated by sex differences in activation of the cardiac renin-angiotensin system.

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Section: Discussionmentioning

confidence: 99%

Sex-dependent impairment of cardiac action potential conduction in type 1 diabetic rats

Shimoni¹,

Emmett²,

Schmidt³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…Whole-cell patch clamp recording Patch-clamp techniques have been described in detail elsewhere [24,25]. Individual currents were normalized to the membrane capacity to control for differences in cell size, being expressed as current density pA/pF.…”

Section: Isolation Of Rabbit Atrial Myocytesmentioning

confidence: 99%

Activation of β<sub>3</sub>-Adrenoceptor Promotes Rapid Pacing-Induced Atrial Electrical Remodeling in Rabbits

et al. 2011

Cell Physiol Biochem

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Cardiac electrophysiological function is under the regulatory control of the sympathetic nervous system. In addition to classical β-adrenoceptors (β-AR, including β₁- and β₂- subtypes), β₃-AR is also expressed in human heart and shows its distinctive functions. This study is aimed to elucidate the role of β₃-AR in the regulation of atrial fibrillation (AF), especially its role in rapid pacing-induced atrial electrical remodeling in rabbits. The rapid atrial pacing model was established by embedding electrodes in the right atrium pacing at a speed of 600 beats per minute. The protein level of β₃-AR in the atria was found significantly upregulated by western blot. The atrial effective refractory period (AERP) and its rate adaptation were decreased after pacing which were further shortened by BRL37344, a selective β₃-AR agonist, leading to the increase of AF inducibility and duration. Similarly, β₃-AR activation induced time-dependent shortening of action potential duration (APD), together with decrease of L-type calcium current (I_Ca,L) and increase of inward rectifier potassium current (I_K1) and transient outward potassium current (I_to) in rapid pacing atrial myocytes. Meanwhile, all the effects were abolished by specific β₃-AR antagonist, SR59230A. In summary, our study represents that activation of β₃-AR promotes the atrial electrical remodeling process by altering the balance of ion channels in atrial myocytes, which provides new insights into the pharmacological role of β₃-AR in heart diseases.

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“…The QT interval reflects the integrated action potential duration (APD) in cardiac myocytes. Ion currents play an important role in cardiac APD, and multiple ion currents are decreased in the experimental animal models of diabetes [5,6]. Therefore, sufficient knowledge of the ionic mechanisms underlying the diabetic QT in diabetes is urgently needed.…”

Section: Introductionmentioning

confidence: 99%

“…It has been reported that the expression of the hERG channel is significantly down-regulated in diabetic hearts, and this down-regulation is a critical contributor to diabetic repolarization slowing and QT prolongation [6,9]. However, there is still an incomplete understanding of the diabetes-induced I Kr /hERG dysfunction.…”

Section: Introductionmentioning

confidence: 99%

High Glucose Represses hERG K+ Channel Expression through Trafficking Inhibition

Shi

Meng

Liu

et al. 2015

Cell Physiol Biochem

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This is an Open Access article licensed under the terms of the Creative Commons AttributionNonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only. Key Words Diabetes mellitus • High-glucose • hERG • LQT • Unfolded protein response • InsulinAbstract Background/Aims: Abnormal QT prolongation is the most prominent cardiac electrical disturbance in patients with diabetes mellitus (DM). It is well known that the human ether-ago-go-related gene (hERG) controls the rapid delayed rectifier K + current (I Kr ) in cardiac cells. The expression of the hERG channel is severely down-regulated in diabetic hearts, and this down-regulation is a critical contributor to the slowing of repolarization and QT prolongation. However, the intracellular mechanisms underlying the diabetes-induced hERG deficiency remain unknown. Methods: The expression of the hERG channel was assessed via western blot analysis, and the hERG current was detected with a patch-clamp technique. Results: The results of our study revealed that the expression of the hERG protein and the hERG current were substantially decreased in high-glucose-treated hERG-HEK cells. Moreover, we demonstrated that the high-glucose-mediated damage to the hERG channel depended on the down-regulation of protein levels but not the alteration of channel kinetics. These discoveries indicated that high glucose likely disrupted hERG channel trafficking. From the western blot and immunoprecipitation analyses, we found that high glucose induced trafficking inhibition through an effect on the expression of Hsp90 and its interaction with hERG. Furthermore, the high-glucose-induced inhibition of hERG channel trafficking could activate the unfolded protein response (UPR) by up-regulating the expression levels of activating transcription factor-6 (ATF-6) and the ER chaperone protein calnexin. In addition, we demonstrated that 100 nM insulin up-regulated the expression of the hERG channel and rescued the hERG channel repression caused by high glucose. Conclusion: The results of our study provide the first evidence of a high-glucose-induced hERG channel deficiency resulting from the inhibition of channel trafficking. Furthermore, insulin promotes the expression of the hERG channel and ameliorates the high-glucose-induced inhibition of the hERG channel.

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Ionic Mechanisms Underlying Abnormal QT Prolongation and the Associated Arrhythmias in Diabetic Rabbits: A Role of Rapid Delayed Rectifier K<sup>+</sup> Current

Cited by 63 publications

References 38 publications

Sex-dependent impairment of cardiac action potential conduction in type 1 diabetic rats

Sex-dependent impairment of cardiac action potential conduction in type 1 diabetic rats

Activation of β<sub>3</sub>-Adrenoceptor Promotes Rapid Pacing-Induced Atrial Electrical Remodeling in Rabbits

High Glucose Represses hERG K+ Channel Expression through Trafficking Inhibition

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