Pathophysiological Remodeling of Mouse Cardiac Myocytes Expressing Dominant Negative Mutant of Neuron Restrictive Silencing Factor

Takano, Makoto; Kinoshita, Hideyuki; Shioya, Takeshi; Itoh, Masayuki; Nakao, Kazuwa; Kuwahara, Koichiro

doi:10.1253/circj.cj-10-0652

Cited by 20 publications

(13 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As we showed previously, 14 the resting membrane potential was somewhat depolarized in ventricular myocytes isolated from dnNRSF-Tg hearts, as compared to WT hearts, which was largely attributed to the decrease in density of inward-rectifier K + current. 24 Ivabradine did not significantly affect the resting membrane potential in dnNRSF-Tg myocytes ( Figure 5E).…”

Section: Ivabradine Reduces the Frequency Of Spontaneous Action Potenmentioning

confidence: 87%

Increased Expression of HCN Channels in the Ventricular Myocardium Contributes to Enhanced Arrhythmicity in Mouse Failing Hearts

Kuwabara

Kuwahara

Takano

et al. 2013

JAHA

Self Cite

View full text Add to dashboard Cite

BackgroundThe efficacy of pharmacological interventions to prevent sudden arrhythmic death in patients with chronic heart failure remains limited. Evidence now suggests increased ventricular expression of hyperpolarization‐activated cation (HCN) channels in hypertrophied and failing hearts contributes to their arrythmicity. Still, the role of induced HCN channel expression in the enhanced arrhythmicity associated with heart failure and the capacity of HCN channel blockade to prevent lethal arrhythmias remains undetermined.Methods and ResultsWe examined the effects of ivabradine, a specific HCN channel blocker, on survival and arrhythmicity in transgenic mice (dnNRSF‐Tg) expressing a cardiac‐specific dominant‐negative form of neuron‐restrictive silencer factor, a useful mouse model of dilated cardiomyopathy leading to sudden death. Ivabradine (7 mg/kg per day orally) significantly reduced ventricular tachyarrhythmias and improved survival among dnNRSF‐Tg mice while having no significant effect on heart rate or cardiac structure or function. Ivabradine most likely prevented the increase in automaticity otherwise seen in dnNRSF‐Tg ventricular myocytes. Moreover, cardiac‐specific overexpression of HCN2 in mice (HCN2‐Tg) made hearts highly susceptible to arrhythmias induced by chronic β‐adrenergic stimulation. Indeed, ventricular myocytes isolated from HCN2‐Tg mice were highly susceptible to β‐adrenergic stimulation‐induced abnormal automaticity, which was inhibited by ivabradine.ConclusionsHCN channel blockade by ivabradine reduces lethal arrhythmias associated with dilated cardiomyopathy in mice. Conversely, cardiac‐specific overexpression of HCN2 channels increases arrhythmogenicity of β‐adrenergic stimulation. Our findings demonstrate the contribution of HCN channels to the increased arrhythmicity seen in failing hearts and suggest HCN channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure.

show abstract

Section: Ivabradine Reduces the Frequency Of Spontaneous Action Potenmentioning

confidence: 87%

Increased Expression of HCN Channels in the Ventricular Myocardium Contributes to Enhanced Arrhythmicity in Mouse Failing Hearts

Kuwabara

Kuwahara

Takano

et al. 2013

JAHA

Self Cite

View full text Add to dashboard Cite

show abstract

“…33, 34 Increased NCX activity can contribute to AP prolongation, repolarization instability, and EAD in HF. 35 In Gαq-TG hearts, (1) TRPC3 and 6 channels were upregulated, (2) SK&F96365 reduced the number of PVC while OAG increased it, (3) EAD-induced triggered activity was frequently observed, and (4) SK&F96365 inhibited EAD. In addition, HF and the prolonged QT interval of ECG were observed in Gαq-TG mice (16 to 34 weeks old) and in our previous studies.…”

Section: Roles Of Trpc Channels In Ventricular Arrhythmias In Gαq-tg mentioning

confidence: 97%

Diacylglycerol Kinase ζ Inhibits Ventricular Tachyarrhythmias in a Mouse Model of Heart Failure

Hirose

Takeishi

Niizeki

et al. 2011

Circ J

View full text Add to dashboard Cite

Background: Diacylglycerol kinase ζ (DGKζ) inhibited atrial tachyarrhythmias in a mouse model of heart failure (HF) in our study. However, whether DGKζ prevents the HF-induced ventricular tachyarrhythmia (VT) is unknown. Methods and Results:Effects of DGKζ on VT using transgenic mice with transient cardiac expression of activated G protein αq (Gαq-TG; model of HF) were elucidated and double transgenic mice with cardiac-specific overexpression of both DGKζ and the activated Gαq (Gαq/DGKζ-TG) were used. Premature ventricular contraction (PVC) and/or VT were frequently observed in Gαq-TG mice but not in Gαq/DGKζ-TG and wild-type (WT) mice (P<0.01). Protein expressions of canonical transient receptor potential (TRPC) channels 3 and 6 increased in Gαq-TG hearts compared with WT and Gαq/DGKζ-TG hearts. SK&F96365, a TRPC channel blocker, decreased the number of PVC and prevented VT in anesthetized Gαq-TG mice (P<0.05). 1-oleoyl-2-acyl-sn-glycerol (OAG), a diacylglycerol analogue, increased the number of PVC in isolated Gαq-TG hearts compared with WT hearts and induced VT in Gαq-TG hearts (P<0.01). SK&F96365 decreased the number of PVC and prevented VT in isolated Gαq-TG hearts (P<0.01) even in the presence of OAG. Early afterdepolarization (EAD)-induced triggered activity was frequently observed in single Gαq-TG ventricular myocytes. Moreover, SK&F96365 prevented the EAD. Conclusions:These results demonstrated that DGKζ inhibited VT in a mouse model of HF and suggest that TRPC channels participate in VT induction in failing hearts. (Circ J 2011; 75: 2333 - 2342

show abstract

“…After deeply anesthetizing mice using 3.0% sevoflurane, their hearts were quickly removed and the ventricular myocytes were isolated through collagenase digestion [12].…”

Section: Cell Isolationmentioning

confidence: 99%

Ectopic automaticity induced in ventricular myocytes by transgenic overexpression of HCN2

Oshita

Itoh

Hirashima

et al. 2015

Journal of Molecular and Cellular Cardiology

Self Cite

View full text Add to dashboard Cite

Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) are expressed in the ventricles of fetal hearts but are normally down-regulated as development progresses. In the hypertrophied heart, however, these channels are re-expressed and generate a hyperpolarization-activated, nonselective cation current (Ih), which evidence suggests may increase susceptibility to arrhythmia. To test this hypothesis, we generated and analyzed transgenic mice overexpressing HCN2 specifically in their hearts (HCN2-Tg). Under physiological conditions, HCN2-Tg mice exhibited no discernible abnormalities. After the application of isoproterenol (ISO), however, ECG recordings from HCN2-Tg mice showed intermittent atrioventricular dissociation followed by idioventricular rhythm. Consistent with this observation, 0.3 μmol/L ISO-induced spontaneous action potentials (SAPs) in 76% of HCN2-Tg ventricular myocytes. In the remaining 24%, ISO significantly depolarized the resting membrane potential (RMP), and the late repolarization phase of evoked action potentials (APs) was significantly longer than in WT myocytes. Analysis of membrane currents revealed that these differences are attributable to the Ih tail current. These findings suggest HCN2 channel activity reduces the repolarization reserve of the ventricular action potential and increases ectopic automaticity under pathological conditions such as excessive β-adrenergic stimulation.

show abstract

Pathophysiological Remodeling of Mouse Cardiac Myocytes Expressing Dominant Negative Mutant of Neuron Restrictive Silencing Factor

Cited by 20 publications

References 25 publications

Increased Expression of HCN Channels in the Ventricular Myocardium Contributes to Enhanced Arrhythmicity in Mouse Failing Hearts

Increased Expression of HCN Channels in the Ventricular Myocardium Contributes to Enhanced Arrhythmicity in Mouse Failing Hearts

Diacylglycerol Kinase ζ Inhibits Ventricular Tachyarrhythmias in a Mouse Model of Heart Failure

Ectopic automaticity induced in ventricular myocytes by transgenic overexpression of HCN2

Contact Info

Product

Resources

About

Pathophysiological Remodeling of Mouse Cardiac Myocytes Expressing Dominant Negative Mutant of Neuron Restrictive Silencing Factor

Cited by 20 publications

References 25 publications

Increased Expression of HCN Channels in the Ventricular Myocardium Contributes to Enhanced Arrhythmicity in Mouse Failing Hearts

Increased Expression of HCN Channels in the Ventricular Myocardium Contributes to Enhanced Arrhythmicity in Mouse Failing Hearts

Diacylglycerol Kinase &zeta; Inhibits Ventricular Tachyarrhythmias in a Mouse Model of Heart Failure

Ectopic automaticity induced in ventricular myocytes by transgenic overexpression of HCN2

Contact Info

Product

Resources

About

Diacylglycerol Kinase ζ Inhibits Ventricular Tachyarrhythmias in a Mouse Model of Heart Failure