Abstract
Tachycardia may cause substantial molecular and ultrastructural alterations in cardiac tissue. The underlying pathophysiology has not been fully explored. The purpose of this study was (I) to validate a three-dimensional in vitro pacing model, (II) to examine the effect of rapid pacing on mitochondrial function in intact cells, and (III) to evaluate the involvement of L-type-channel-mediated calcium influx in alterations of mitochondria in cardiomyocytes during rapid pacing. In vitro differentiated cardiomyocytes from P19 cells that formed embryoid bodies were paced for 24 h with 0.6 and 2.0 Hz. Pacing at 2.0 Hz increased mRNA expression and phosphorylation of ERK1/2 and caused cellular hypertrophy, indicated by increased protein/DNA ratio, and oxidative stress measured as loss of cellular thiols. Rapid pacing additionally provoked structural alterations of mitochondria. All these changes are known to occur in vivo during atrial fibrillation. The structural alterations of mitochondria were accompanied by limitation of ATP production as evidenced by decreased endogenous respiration in combination with decreased ATP levels in intact cells. Inhibition of calcium inward current with verapamil protected against hypertrophic response and oxidative stress. Verapamil ameliorated morphological changes and dysfunction of mitochondria. In conclusion, rapid pacing-dependent changes in calcium inward current via L-type channels mediate both oxidative stress and mitochondrial dysfunction. The in vitro pacing model presented here reflects changes occurring during tachycardia and, thus, allows functional analyses of the signaling pathways involved.
Original language | English (US) |
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Pages (from-to) | 608-615 |
Number of pages | 8 |
Journal | Biochimica et Biophysica Acta - Molecular Basis of Disease |
Volume | 1762 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2006 |
Bibliographical note
Funding Information:We thank Katja Mook, Regine Widmayer, Karla Klingenberg, and Cornelia Müller for excellent technical assistance. This work was supported by grants from the “Kultusministerium des Landes Sachsen-Anhalt, Germany” (3517 A/0603M) and by the “Bundesministerium für Bildung und Forschung, Germany” (grant 01ZZ0407 and Kompetenznetz Vorhofflimmern, grant 01GI 0204).
Keywords
- Arrhythmia
- Hypertrophy
- Mitochondria
- Myocyte
- Oxidative stress
- Pacing