Reduced expression of HCN channels in the sinoatrial node of streptozotocin-induced diabetic rats

Huang, Xin; Zhong, Nier; Zhang, Hong; Ma, Aiqun; Yuan, Zuyi; Guo, Ning

doi:10.1139/cjpp-2016-0418

Cited by 15 publications

(22 citation statements)

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“…This study has shown downregulation of key ion channels proteins important for healthy functioning of the CCS. Previous research has shown significant downregulation of HCN4 in the SAN of STZ rat heart (Huang et al, 2017). Our study has also demonstrated that HCN4 is downregulated in the SAN in the STZ rat compared to controls.…”

Section: Discussionmentioning

confidence: 80%

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Electrical Conduction System Remodeling in Streptozotocin-Induced Diabetes Mellitus Rat Heart

et al. 2019

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Cardiovascular complications are common in type 1 diabetes mellitus (TIDM) and there is an increased risk of arrhythmias as a result of dysfunction of the cardiac conduction system (CCS). We have previously shown that, in vivo , there is a decrease in the heart rate and prolongation of the QRS complex in streptozotocin-induced type 1 diabetic rats indicating dysfunction of the CCS. The aim of this study was to investigate the function of the ex vivo CCS and key proteins that are involved in pacemaker mechanisms in TIDM. RR interval, PR interval and QRS complex duration were significantly increased in diabetic rats. The beating rate of the isolated sinoatrial node (SAN) preparation was significantly decreased in diabetic rats. The funny current density and cell capacitance were significantly decreased in diabetic nodal cells. Western blot showed that proteins involved in the function of the CCS were significantly decreased in diabetic rats, namely: HCN4, Ca v 1.3, Ca v 3.1, Cx45, and NCX1 in the SAN; RyR2 and NCX1 in the atrioventricular junction and Cx40, Cx43, Cx45, and RyR2 in the Purkinje network. We conclude that there are complex functional and cellular changes in the CCS in TIDM. The changes in the proteins involved in the function of this electrical system are expected to adversely affect action potential generation and propagation, and these changes are likely to be arrhythmogenic.

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Section: Discussionmentioning

confidence: 80%

“…Cardiac remodeling and altered expression of ion channels may be involved in setting the cardiac rate and rhythm (Movahed, 2007). We have previously shown that TIDM affects a range of mRNA expression in the diabetic SAN (NCX1, Cx45, Ca v 3.1, and HCN4) (Ferdous et al, 2016; Huang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Electrical Conduction System Remodeling in Streptozotocin-Induced Diabetes Mellitus Rat Heart

et al. 2019

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“…Streptozotocin (STZ)-induced diabetic rats have a lower intrinsic heart rate, an inferior leading pacemaker site, reduced sinoatrial node (SAN) conduction velocity and diastolic depolarization slope, and a longer action potential duration than in the control. The transcripts and proteins of HCN2 and HCN4 in diabetic SAN are reduced, suggesting possible involvement of HCN channels in diabetes-related cardiac problems 91 . In diabetes, bladder Cajal-like interstitial cells are impaired and recently, HCN channels expression associated with caveolae and caveolin was found to be decreased too, suggesting this as one of the molecular mechanisms underlying diabetic bladder problems 92 .…”

Section: Recent Studies and Future Directionsmentioning

confidence: 99%

Advances in Understanding of Structure, Function and Plasticity of HCN Channels

Khurana

2018

Current Science

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Hyperpolarization-activated, cyclic nucleotide-sensitive, cation non-selective (HCN) channels are gaining attention in recent years. These ion-channels are gated by two factors: voltage, specifically hyperpolarization and some subunits, more than others, by cyclic nucleotides. They conduct both sodium and potassium ions, and regulate many functions in both neuronal and non-neuronal cells. In neurons, HCN channel functions range from setting resting potential, synaptic normalization, gain control, after-hyperpolarization, setting responses in dendrites, mediating cannabinoid role in neuronal plasticity to the gating of plasticity. Emerging properties of circuits expressing HCN channels manifest in the form of various kinds of functions like brain rhythms, perception, spatial learning, executive memory, epilepsy, ataxia, depression, sound localization, anxiety, etc. We are beginning to understand the roles of these channels in nonneuronal cells and we would discover more such roles in the future. Following ischaemia, there is HCN overexpression in the reactive astrocytes. There is an altered expression of HCN channels in few tissues in diabetic animal models. Recent evidence suggests that HCN channels are also involved in uterine contractions and renal functioning. This review focuses on the function, structure, interacting proteins and developmental plasticity that enable the versatility of HCN channels.

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“…Interestingly, although clinical studies reported efficacy and safety of ivabradine in diabetic patients [21], cardiac effects of ivabradine have been reported to be weaker in rats with streptozotocin (STZ)-induced diabetic heart damage [22]. Recently, reduced expression of HCN channels in the sinoatrial node of streptozotocin (STZ)-induced diabetic rats was found [20]. Therefore, we hypothesize that altered cardiac electrogenesis in diabetes might be affected by changes in cardiac HCN channel expression.…”

mentioning

confidence: 98%

“…Furthermore, I f augmentation induces a diastolic influx of Na + cations leading to increased intracellular Ca 2+ due to the Na + / Ca 2+ exchanger shift towards 'reverse mode' resulting in increased arrhythmogenicity [16]. The overexpression of myocardial HCN occurs in various conditions, including cardiac hypertrophy [17], acute myocardial infarction [18] and heart failure [15] while the reduction of myocardial HCN is rather related to atria and to impaired sinus rhythm [19,20].…”

mentioning

confidence: 99%

Isolated downregulation of HCN2 in ventricles of rats with streptozotocin-induced diabetic cardiomyopathy

Hadova

Kráľová

Doka

et al. 2021

BMC Cardiovasc Disord

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Background In spite of disrupted repolarization of diabetic heart, some studies report less tendency of diabetic heart to develop ventricular arrhythmias suggesting effective compensatory mechanism. We hypothesized that myocardial alterations in HCN2 and HCN4 channels occur under hyperglycaemia. Methods Diabetes was induced in rats using a single injection of streptozotocin (STZ; 55 mg/kg body weight, i.p.). Basal ECG was measured. Expression of mRNA for HCN channels, potassium channels and microRNA 1 and 133a were measured in ventricular tissues. Protein expression of HCN2 channel isoform was assessed in five different regions of the heart by western blotting. Differentiated H9c2 cell line was used to examine HCN channels expression under hyperglycaemia in vitro. Results Six weeks after STZ administration, heart rate was reduced, QRS complex duration, QT interval and T-wave were prolonged in diabetic rats compared to controls. mRNA and protein expressions of HCN2 decreased exclusively in the ventricles of diabetic rats. HCN2 expression levels in atria of STZ rats and H9c2 cells treated with excess of glucose were not changed. MicroRNA levels were stable in STZ rat hearts. We found significantly decreased mRNA levels of several potassium channels participating in repolarization, namely Kcnd2 (Ito1), Kcnh2 (IKr), Kcnq1 (IKs) and Kcnj11 (IKATP). Conclusions This result together with downregulated HCN2 channels suggest that HCN channels might be an integral part of ventricular electric remodelling and might play a role in cardiac repolarization projected in altered arrhythmogenic profile of diabetic heart.

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Reduced expression of HCN channels in the sinoatrial node of streptozotocin-induced diabetic rats

Cited by 15 publications

References 51 publications

Electrical Conduction System Remodeling in Streptozotocin-Induced Diabetes Mellitus Rat Heart

Electrical Conduction System Remodeling in Streptozotocin-Induced Diabetes Mellitus Rat Heart

Advances in Understanding of Structure, Function and Plasticity of HCN Channels

Isolated downregulation of HCN2 in ventricles of rats with streptozotocin-induced diabetic cardiomyopathy

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