The functional consequences of sodium channel NaV1.8 in human left ventricular hypertrophy
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The functional consequences of sodium channel NaV1.8 in human left ventricular hypertrophy. / Ahmad, Shakil; Tirilomis, Petros; Pabel, Steffen; Dybkova, Nataliya; Hartmann, Nico; Molina, Cristina E.; Tirilomis, Theodoros; Kutschka, Ingo; Frey, Norbert; Maier, Lars S.; Hasenfuss, Gerd; Streckfuss-Bömeke, Katrin; Sossalla, Samuel.
in: ESC HEART FAIL, Jahrgang 6, Nr. 1, 02.2019, S. 154-163.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - The functional consequences of sodium channel NaV1.8 in human left ventricular hypertrophy
AU - Ahmad, Shakil
AU - Tirilomis, Petros
AU - Pabel, Steffen
AU - Dybkova, Nataliya
AU - Hartmann, Nico
AU - Molina, Cristina E.
AU - Tirilomis, Theodoros
AU - Kutschka, Ingo
AU - Frey, Norbert
AU - Maier, Lars S.
AU - Hasenfuss, Gerd
AU - Streckfuss-Bömeke, Katrin
AU - Sossalla, Samuel
N1 - © 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.
PY - 2019/2
Y1 - 2019/2
N2 - AIMS: In hypertrophy and heart failure, the proarrhythmic persistent Na + current (I NaL ) is enhanced. We aimed to investigate the electrophysiological role of neuronal sodium channel Na V 1.8 in human hypertrophied myocardium. METHODS AND RESULTS: Myocardial tissue of 24 patients suffering from symptomatic severe aortic stenosis and concomitant significant afterload-induced hypertrophy with preserved ejection fraction was used and compared with 12 healthy controls. We performed quantitative real-time PCR and western blot and detected a significant up-regulation of Na V 1.8 mRNA (2.34-fold) and protein expression (1.96-fold) in human hypertrophied myocardium compared with healthy hearts. Interestingly, Na V 1.5 protein expression was significantly reduced in parallel (0.60-fold). Using whole-cell patch-clamp technique, we found that the prominent I NaL was significantly reduced after addition of novel Na V 1.8-specific blockers either A-803467 (30 nM) or PF-01247324 (1 μM) in human hypertrophic cardiomyocytes. This clearly demonstrates the relevant contribution of Na V 1.8 to this proarrhythmic current. We observed a significant action potential duration shortening and performed confocal microscopy, demonstrating a 50% decrease in proarrhythmic diastolic sarcoplasmic reticulum (SR)-Ca 2+ leak and SR-Ca 2+ spark frequency after exposure to both Na V 1.8 inhibitors. CONCLUSIONS: We show for the first time that the neuronal sodium channel Na V 1.8 is up-regulated on mRNA and protein level in the human hypertrophied myocardium. Furthermore, inhibition of Na V 1.8 reduced augmented I NaL , abbreviated the action potential duration, and decreased the SR-Ca 2+ leak. The findings of our study suggest that Na V 1.8 could be a promising antiarrhythmic therapeutic target and merits further investigation.
AB - AIMS: In hypertrophy and heart failure, the proarrhythmic persistent Na + current (I NaL ) is enhanced. We aimed to investigate the electrophysiological role of neuronal sodium channel Na V 1.8 in human hypertrophied myocardium. METHODS AND RESULTS: Myocardial tissue of 24 patients suffering from symptomatic severe aortic stenosis and concomitant significant afterload-induced hypertrophy with preserved ejection fraction was used and compared with 12 healthy controls. We performed quantitative real-time PCR and western blot and detected a significant up-regulation of Na V 1.8 mRNA (2.34-fold) and protein expression (1.96-fold) in human hypertrophied myocardium compared with healthy hearts. Interestingly, Na V 1.5 protein expression was significantly reduced in parallel (0.60-fold). Using whole-cell patch-clamp technique, we found that the prominent I NaL was significantly reduced after addition of novel Na V 1.8-specific blockers either A-803467 (30 nM) or PF-01247324 (1 μM) in human hypertrophic cardiomyocytes. This clearly demonstrates the relevant contribution of Na V 1.8 to this proarrhythmic current. We observed a significant action potential duration shortening and performed confocal microscopy, demonstrating a 50% decrease in proarrhythmic diastolic sarcoplasmic reticulum (SR)-Ca 2+ leak and SR-Ca 2+ spark frequency after exposure to both Na V 1.8 inhibitors. CONCLUSIONS: We show for the first time that the neuronal sodium channel Na V 1.8 is up-regulated on mRNA and protein level in the human hypertrophied myocardium. Furthermore, inhibition of Na V 1.8 reduced augmented I NaL , abbreviated the action potential duration, and decreased the SR-Ca 2+ leak. The findings of our study suggest that Na V 1.8 could be a promising antiarrhythmic therapeutic target and merits further investigation.
KW - Left ventricular hypertrophy, Sodium channels, Late sodium current, HFpEF, Arrhythmias, Calcium, SR-Ca2+ leak
KW - Action Potentials
KW - Aged
KW - Blotting, Western
KW - Diastole
KW - Female
KW - Gene Expression Regulation
KW - Heart Ventricles/metabolism
KW - Humans
KW - Hypertrophy, Left Ventricular/diagnosis
KW - Male
KW - Myocytes, Cardiac/metabolism
KW - NAV1.8 Voltage-Gated Sodium Channel/biosynthesis
KW - Patch-Clamp Techniques
KW - RNA/genetics
KW - Real-Time Polymerase Chain Reaction
KW - Sarcoplasmic Reticulum/metabolism
U2 - 10.1002/ehf2.12378
DO - 10.1002/ehf2.12378
M3 - SCORING: Journal article
C2 - 30378291
VL - 6
SP - 154
EP - 163
JO - ESC HEART FAIL
JF - ESC HEART FAIL
SN - 2055-5822
IS - 1
ER -