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

Abstract

(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...

Impact of Metabolic Syndrome on Left Atrial Electroanatomical Remodeling and Outcomes After Radiofrequency Ablation of Nonvalvular Atrial Fibrillation

“…Through associated oxidative stress and unfavorable hemodynamic, metabolic, and cytokine influences, MetS leads to development of atrial fibrosis and slow conduction that can be visualized in LA voltage maps as areas of fractionated and low voltage potentials. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] Our study demonstrated that advanced electric remodeling and the presence of nonpulmonary vein substrate for AF must be expected in MetS and that the presence and extent of LA low voltage areas were associated with more AF recurrences, a finding supported by a previous study. 32 We suggest that in addition to PVI, extensive ablation to modify these low voltage areas may be necessary to achieve better long-term outcomes in patients with MetS.…”

“…[1][2][3][4][5] Renin-angiotensin system and oxidative stress can change the membrane ion channels and modulate the connexin surface expression, leading to slow atrial conduction. [6][7][8][9][10][11][12] This process called electroanatomic remodeling is frequently observed in patients with atrial fibrillation (AF). 13 Increased collagen deposition and matrix volume expansion has been found to correlate with the presence of AF and its persistence.…”

Voltage-Gated Sodium Channel Nav1.7 Maintains the Membrane Potential and Regulates the Activation and Chemokine-Induced Migration of a Monocyte-Derived Dendritic Cell Subset

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NADPH oxidase signaling and cardiac myocyte function

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