Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 294, Issue 1, Pages C372-C379Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00186.2007
Keywords
arrhythmia; gene expression; sodium channel; redox signaling; renin angiotensin system
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Funding
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL073753, R01HL064828, R01HL085558] Funding Source: NIH RePORTER
- NHLBI NIH HHS [R01 HL073753, HL-73753, R01 HL085558-04, HL-64828, R01 HL085558, R01 HL064828] Funding Source: Medline
- PHS HHS [F32] Funding Source: Medline
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Angiotensin II (ANG II) increases oxidative stress and is associated with increased risk of sudden cardiac death. The cardiac Na+ channel promoter contains elements that confer redox sensitivity. We tested the hypothesis that ANG II-mediated oxidative stress may modulate Na+ channel current through altering channel transcription. In H9c2 myocytes treated for 48 h with ANG II (100 nmol/l) or H2O2 (10 mu mol/l) showed delayed macroscopic inactivation, increased late current, and 59.6% and 53.8% reductions in Na+ current, respectively (P <= 0.01). By quantitative real- time RT- PCR, the cardiac Na+ channel (scn5a) mRNA abundance declined by 47.3% (P < 0.01) in H9c2 myocytes treated for 48 h with 100 nmol/l ANG II. A similar change occurred with 20 mu mol/l H2O2 (46.9%, P < 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-kappa B binding site prevented decreased activity in response to ANG II and H2O2. Gel shift and chromosomal immunoprecipitation assays confirmed that nuclear factor (NF)-kappa B bound to the scn5a promoter in response to ANG II and H2O2. Overexpression of the p50 subunit of NF-kappa B in H9c2 cells reduced scn5a mRNA (77.3%, P < 0.01). In conclusion, ANG II can decrease scn5a transcription and current. This effect appears to be through production of H2O2 resulting in NF-kappa B binding to the Na+ channel promoter.
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