Human Heart Failure Is Associated With Abnormal C-Terminal Splicing Variants in the Cardiac Sodium Channel

Shang, Lijuan L.; Pfahnl, Arnold; Sanyal, Shamarendra; Jing, Zhe; Allen, Julie; Banach, Kathrin; Fahrenbach, John; Weiss, Daiana; Taylor, W. Robert; Zafari, A. Maziar; Dudley, Samuel C.

doi:10.1161/circresaha.107.152918

Cited by 115 publications

(118 citation statements)

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“…Splicing events in HF generate multiple sodium channel protein isoforms, some of which lead to less functional channels and modify the gating properties of the overall I Na 43, 44. Glycosylation of the sodium channel is known to modulate I Na and its gating properties, and underlies arrhythmogenesis in HF 45, 46.…”

Section: Discussionmentioning

confidence: 99%

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

Rivaud

Agullo‐Pascual

Lin

et al. 2017

JAHA

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BackgroundCardiac sodium channel (NaV1.5) dysfunction contributes to arrhythmogenesis during pathophysiological conditions. Nav1.5 localizes to distinct subcellular microdomains within the cardiomyocyte, where it associates with region‐specific proteins, yielding complexes whose function is location specific. We herein investigated sodium channel remodeling within distinct cardiomyocyte microdomains during heart failure.Methods and ResultsMice were subjected to 6 weeks of transverse aortic constriction (TAC; n=32) to induce heart failure. Sham–operated on mice were used as controls (n=20). TAC led to reduced left ventricular ejection fraction, QRS prolongation, increased heart mass, and upregulation of prohypertrophic genes. Whole‐cell sodium current (INa) density was decreased by 30% in TAC versus sham–operated on cardiomyocytes. On macropatch analysis, INa in TAC cardiomyocytes was reduced by 50% at the lateral membrane (LM) and by 40% at the intercalated disc. Electron microscopy and scanning ion conductance microscopy revealed remodeling of the intercalated disc (replacement of [inter‐]plicate regions by large foldings) and LM (less identifiable T tubules and reduced Z‐groove ratios). Using scanning ion conductance microscopy, cell‐attached recordings in LM subdomains revealed decreased INa and increased late openings specifically at the crest of TAC cardiomyocytes, but not in groove/T tubules. Failing cardiomyocytes displayed a denser, but more stable, microtubule network (demonstrated by increased α‐tubulin and Glu‐tubulin expression). Superresolution microscopy showed reduced average NaV1.5 cluster size at the LM of TAC cells, in line with reduced INa.ConclusionsHeart failure induces structural remodeling of the intercalated disc, LM, and microtubule network in cardiomyocytes. These adaptations are accompanied by alterations in NaV1.5 clustering and INa within distinct subcellular microdomains of failing cardiomyocytes.

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Section: Discussionmentioning

confidence: 99%

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

Rivaud

Agullo‐Pascual

Lin

et al. 2017

JAHA

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“…4 More recently, changes in SCN5A (expression, splicing, posttranslational modifications including CaMKII phosphorylation) and/or its ␤-subunits that decrease peak I Na or increase I Na,L have been implicated as potential contributing factors for more common types of sudden death from acquired heart diseases such as heart failure. [5][6][7][8] Articles, see p 322 and 333…”

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Whither Art Thou, SCN10A, and What Art Thou Doing?

London

2012

Circulation Research

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Since its initial cloning in 1992, SCN5A (Nav1.5) has become known as "the" cardiac sodium channel. 1 SCN5A encodes a tetrodotoxin (TTX)-resistant channel that is responsible for the inward sodium current (I Na ), which initiates the cardiac action potential. Its RNA and protein expression dominate the sodium channel landscape in the ventricle, atrium, and specialized conduction system. Mice heterozygous for a targeted Scn5a deletion (Scn5a ϩ/Ϫ mice) have slowed conduction along with atrial and ventricular arrhythmias, whereas homozygous targeted deletion in mice is embryonic lethal. 2 In humans, pharmacological agents that block SCN5A such as flecainide, developed as antiarrhythmics, are proarrhythmic and increase mortality in patients with structural heart disease. 3 In addition, SCN5A mutations cause a potpourri of diseases that lead to sudden cardiac death including long-QT syndrome type 3 (LQT3, gain-of-function mutations that slow inactivation and increase late sodium current, I Na,L ), Brugada syndrome (BRS1, loss of function mutations that decrease peak I Na ), conduction disease, atrial fibrillation, and dilated cardiomyopathy. 4 More recently, changes in SCN5A (expression, splicing, posttranslational modifications including CaMKII phosphorylation) and/or its ␤-subunits that decrease peak I Na or increase I Na,L have been implicated as potential contributing factors for more common types of sudden death from acquired heart diseases such as heart failure. 5-8 Articles, see p 322 and 333A number of independent lines of evidence have suggested that other sodium channels might play important roles in the heart. In the mouse, Scn5a is preferentially localized at intercalated disks, whereas Nav1.1, Nav1.3, and Nav1.6 are localized in t-tubules. 9 Consistent with this, TTX-sensitive sodium channels were shown to be responsible for 16% of the sodium channel mRNA and 8% of the peak I Na in isolated adult cardiac myocytes and were upregulated in cardiac myocytes isolated from rats with thoracic aortic bandinginduced heart failure and increased I Na,L . 10,11 SCN10A (Nav1.8) is another TTX-resistant sodium channel located adjacent to SCN5A on human chromosome 3p21-22 that was originally identified in neurons. 12,13 Scn10a mRNA is also expressed in both in isolated mouse atrial and ventricular myocytes, and Scn10a Ϫ/Ϫ mice have shorter PR intervals during ambulatory telemetry monitoring than wild-type littermates. In contrast, other investigators have shown that wild-type mice treated acutely with the Scn10a-specific blocker A-803467 have longer PR and wider QRS intervals during both ambulatory telemetry monitoring and invasive electrophysiology studies. 14 Thus, the molecular evidence favors a role for other sodium channels in general and Scn10a in particular in the rodent heart. SCN10A mRNA is also expressed in human heart tissue. 13 Unexpectedly, evidence for a role for SCN10A in human cardiac electrophysiology came from genome-wide association studies (GWAS). Using PR and/or QRS intervals as intermediate phenot...

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“…Downregulations of Na ϩ channels and connexin 43 are seen in heart failure, a condition associated with increased RAS activation (4, 15,37,46). Moreover, forms of electrical remodeling can be inhibited by agents altering RAS signaling and by antioxidants (8,24,38), suggesting that ANG IImediated ion channel transcriptional changes may contribute to arrhythmic risk.…”

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confidence: 99%

NF-κB-dependent transcriptional regulation of the cardiac scn5a sodium channel by angiotensin II

Shang¹,

Sanyal²,

Pfahnl³

et al. 2008

American Journal of Physiology-Cell Physiology

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106

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(ANG II) increases oxidative stress and is associated with increased risk of sudden cardiac death. The cardiac Na ϩ channel promoter contains elements that confer redox sensitivity. We tested the hypothesis that ANG IImediated oxidative stress may modulate Na ϩ channel current through altering channel transcription. In H9c2 myocytes treated for 48 h with ANG II (100 nmol/l) or H2O2 (10 mol/l) showed delayed macroscopic inactivation, increased late current, and 59.6% and 53.8% reductions in Na ϩ current, respectively (P Յ 0.01). By quantitative real-time RT-PCR, the cardiac Na ϩ channel (scn5a) mRNA abundance declined by 47.3% (P Ͻ 0.01) in H9c2 myocytes treated for 48 h with 100 nmol/l ANG II. A similar change occurred with 20 mol/l H2O2 (46.9%, P Ͻ 0.01) after 48 h. Comparable effects were seen in acutely isolated ventricular myocytes. The effects of ANG II could be inhibited by prior treatment of H9c2 cells with scavengers of reactive oxygen species or an inhibitor of the NADPH oxidase. Mutation of the scn5a promoter NF-B binding site prevented decreased activity in response to ANG II and H2O2. Gel shift and chromosomal immunoprecipitation assays confirmed that nuclear factor (NF)-B bound to the scn5a promoter in response to ANG II and H2O2. Overexpression of the p50 subunit of NF-B in H9c2 cells reduced scn5a mRNA (77.3%, P Ͻ 0.01). In conclusion, ANG II can decrease scn5a transcription and current. This effect appears to be through production of H2O2 resulting in NF-B binding to the Na ϩ channel promoter. arrhythmia, gene expression; sodium channel; redox signaling; renin angiotensin system ACTIVATION of the renin-angiotensin system (RAS) has been implicated in arrhythmia associated with heart failure because inhibitors of this pathway reduce the incidence of sudden death (18,39,42,43). One major effecter of RAS activation is angiotensin II (ANG II), produced by enzymatic activity of angiotensin-converting enzyme (ACE) on angiotensin I. ANG II is known to increase oxidative stress through NADPH oxidase activation (7,20,31). Increased oxygen free radical production is associated with congestive heart failure (13, 21) and arrhythmias (6, 32). Nevertheless, the molecular basis whereby ANG II may cause arrhythmias and any role for ANG II-induced oxidative stress are not clear.Ion channel transcriptional regulation is implicated in increasing ventricular and atrial arrhythmic risk (1,9,25,29,44).Often referred to as electrical remodeling, the changes in myocyte electrical properties in states of increased arrhythmic risk are related to underlying changes in expression of several ion channel genes, including reductions in connexins and Na ϩ channels, and may be responsible for the arrhythmic effects of ANG II. Downregulations of Na ϩ channels and connexin 43 are seen in heart failure, a condition associated with increased RAS activation (4, 15, 37, 46). Moreover, forms of electrical remodeling can be inhibited by agents altering RAS signaling and by antioxidants (8,24,38), suggesting that ANG IImediated ion channe...

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Human Heart Failure Is Associated With Abnormal C-Terminal Splicing Variants in the Cardiac Sodium Channel

Cited by 115 publications

References 48 publications

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

Whither Art Thou, SCN10A, and What Art Thou Doing?

NF-κB-dependent transcriptional regulation of the cardiac scn5a sodium channel by angiotensin II

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