Ahmad, Shakil and Tirilomis, Petros and Pabel, Steffen and Dybkova, Nataliya and Hartmann, Nico and Molina, Cristina E. and Tirilomis, Theodoros and Kutschka, Ingo and Frey, Norbert and Maier, Lars S. and Hasenfuss, Gerd and Streckfuss-Boemeke, Katrin and Sossalla, Samuel (2019) The functional consequences of sodium channel Na(V)1.8 in human left ventricular hypertrophy. ESC HEART FAILURE, 6 (1). pp. 154-163. ISSN 2055-5822,
Full text not available from this repository. (Request a copy)Abstract
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 mu M) 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)-Ca2+ leak and SR-Ca2+ 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-Ca2+ leak. The findings of our study suggest that Na(V)1.8 could be a promising antiarrhythmic therapeutic target and merits further investigation.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HEART-FAILURE; DYSFUNCTION; MYOCARDIUM; EXPRESSION; MYOCYTES; BLOCKER; Left ventricular hypertrophy; Sodium channels; Late sodium current; HFpEF; Arrhythmias; Calcium; SR-Ca2+ leak |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 Apr 2020 05:21 |
| Last Modified: | 20 Apr 2020 05:21 |
| URI: | https://pred.uni-regensburg.de/id/eprint/27619 |
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