Dataset Information

Post-transcriptional silencing of SCN1B and SCN2B genes modulates late sodium current in cardiac myocytes from normal dogs and dogs with chronic heart failure.

ABSTRACT: The emerging paradigm for Na(+) current in heart failure (HF) is that its transient component (I(NaT)) responsible for the action potential (AP) upstroke is decreased, whereas the late component (I(NaL)) involved in AP plateau is augmented. Here we tested whether Na(v)?(1)- and Na(v)?(2)-subunits can modulate I(NaL) parameters in normal and failing ventricular cardiomyocytes (VCMs). Chronic HF was produced in nine dogs by multiple sequential coronary artery microembolizations, and six dogs served as a control. I(Na) and APs were measured by the whole cell and perforated patch-clamp in freshly isolated and cultured VCMs, respectively. I(NaL) was augmented with slower decay in HF VCMs compared with normal heart VCMs, and these properties remained unchanged within 5 days of culture. Post-transcriptional silencing SCN1B and SCN2B were achieved by virally delivered short interfering RNA (siRNA) specific to Na(v)?(1) and Na(v)?(2). The delivery and efficiency of siRNA were evaluated by green fluorescent protein expression, by the real-time RT-PCR, and Western blots, respectively. Five days after infection, the levels of mRNA and protein for Na(v)?(1) and Na(v)?(2) were reduced by >80%, but mRNA and protein of Na(v)1.5, as well as I(NaT), remained unchanged in HF VCMs. Na(v)?(1)-siRNA reduced I(NaL) density and accelerated I(NaL) two-exponential decay, whereas Na(v)?(2)-siRNA produced an opposite effect in VCMs from both normal and failing hearts. Physiological importance of the discovered I(NaL) modulation to affect AP shape and duration was illustrated both experimentally and by numerical simulations of a VCM excitation-contraction coupling model. We conclude that in myocytes of normal and failing dog hearts Na(v)?(1) and Na(v)?(2) exhibit oppositely directed modulation of I(NaL).

SUBMITTER: Mishra S

PROVIDER: S-EPMC3197374 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Post-transcriptional silencing of SCN1B and SCN2B genes modulates late sodium current in cardiac myocytes from normal dogs and dogs with chronic heart failure.

Mishra Sudhish S Undrovinas Nidas A NA Maltsev Victor A VA Reznikov Vitaliy V Sabbah Hani N HN Undrovinas Albertas A

American journal of physiology. Heart and circulatory physiology 20110624 4

The emerging paradigm for Na(+) current in heart failure (HF) is that its transient component (I(NaT)) responsible for the action potential (AP) upstroke is decreased, whereas the late component (I(NaL)) involved in AP plateau is augmented. Here we tested whether Na(v)β(1)- and Na(v)β(2)-subunits can modulate I(NaL) parameters in normal and failing ventricular cardiomyocytes (VCMs). Chronic HF was produced in nine dogs by multiple sequential coronary artery microembolizations, and six dogs serve ...[more]

PMID: 21705762

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Project description:Heart failure constitutes a major public health problem worldwide. The electrophysiological remodeling of failing hearts sets the stage for malignant arrhythmias, in which the role of the late Na(+) current (I(NaL)) is relevant and is currently under investigation. In this study we examined the role of I(NaL) in the electrophysiological phenotype of ventricular myocytes, and its proarrhythmic effects in the failing heart. A model for cellular heart failure was proposed using a modified version of Grandi et al. model for human ventricular action potential that incorporates the formulation of I(NaL). A sensitivity analysis of the model was performed and simulations of the pathological electrical activity of the cell were conducted. The proposed model for the human I(NaL) and the electrophysiological remodeling of myocytes from failing hearts accurately reproduce experimental observations. The sensitivity analysis of the modulation of electrophysiological parameters of myocytes from failing hearts due to ion channels remodeling, revealed a role for I(NaL) in the prolongation of action potential duration (APD), triangulation of the shape of the AP, and changes in Ca(2+) transient. A mechanistic investigation of intracellular Na(+) accumulation and APD shortening with increasing frequency of stimulation of failing myocytes revealed a role for the Na(+)/K(+) pump, the Na(+)/Ca(2+) exchanger and I(NaL). The results of the simulations also showed that in failing myocytes, the enhancement of I(NaL) increased the reverse rate-dependent APD prolongation and the probability of initiating early afterdepolarizations. The electrophysiological remodeling of failing hearts and especially the enhancement of the I(NaL) prolong APD and alter Ca(2+) transient facilitating the development of early afterdepolarizations. An enhanced I(NaL) appears to be an important contributor to the electrophysiological phenotype and to the dysregulation of [Ca(2+)](i) homeostasis of failing myocytes.

Dataset Information

Post-transcriptional silencing of SCN1B and SCN2B genes modulates late sodium current in cardiac myocytes from normal dogs and dogs with chronic heart failure.

Publications

Post-transcriptional silencing of SCN1B and SCN2B genes modulates late sodium current in cardiac myocytes from normal dogs and dogs with chronic heart failure.

Similar Datasets

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