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Inhibiting Na+/K+ ATPase can impair mitochondrial energetics and induce abnormal Ca2+ cycling and automaticity in guinea pig cardiomyocytes
- Source :
- PLoS ONE, PLoS ONE, Vol 9, Iss 4, p e93928 (2014)
- Publication Year :
- 2013
-
Abstract
- Cardiac glycosides have been used for the treatment of heart failure because of their capabilities of inhibiting Na+/K+ ATPase (NKA), which raises [Na+]i and attenuates Ca2+ extrusion via the Na+/Ca2+ exchanger (NCX), causing [Ca2+]i elevation. The resulting [Ca2+]i accumulation further enhances Ca2+-induced Ca2+ release, generating the positive inotropic effect. However, cardiac glycosides have some toxic and side effects such as arrhythmogenesis, confining their extensive clinical applications. The mechanisms underlying the proarrhythmic effect of glycosides are not fully understood. Here we investigated the mechanisms by which glycosides could cause cardiac arrhythmias via impairing mitochondrial energetics using an integrative computational cardiomyocyte model. In the simulations, the effect of glycosides was mimicked by blocking NKA activity. Results showed that inhibiting NKA not only impaired mitochondrial Ca2+ retention (thus suppressed reactive oxygen species (ROS) scavenging) but also enhanced oxidative phosphorylation (thus increased ROS production) during the transition of increasing workload, causing oxidative stress. Moreover, concurrent blocking of mitochondrial Na+/Ca2+ exchanger, but not enhancing of Ca2+ uniporter, alleviated the adverse effects of NKA inhibition. Intriguingly, NKA inhibition elicited Ca2+ transient and action potential alternans under more stressed conditions such as severe ATP depletion, augmenting its proarrhythmic effect. This computational study provides new insights into the mechanisms underlying cardiac glycoside-induced arrhythmogenesis. The findings suggest that targeting both ion handling and mitochondria could be a very promising strategy to develop new glycoside-based therapies in the treatment of heart failure.
- Subjects :
- Physiology
ATPase
lcsh:Medicine
Action Potentials
Mitochondrion
Pharmacology
medicine.disease_cause
Biochemistry
Antioxidants
Oxidative Phosphorylation
Membrane Potentials
Adenosine Triphosphate
Medicine and Health Sciences
Homeostasis
Myocytes, Cardiac
lcsh:Science
Inner mitochondrial membrane
Multidisciplinary
biology
Chemistry
Cell biology
Mitochondria
Electrophysiology
Cardiovascular Diseases
Engineering and Technology
Sodium-Potassium-Exchanging ATPase
Arrhythmia
Research Article
Biotechnology
Biophysical Simulations
Guinea Pigs
Biophysics
Biomedical Engineering
Cardiology
Bioengineering
Oxidative phosphorylation
Bioenergetics
medicine
Animals
Computer Simulation
Na+/K+-ATPase
Uniporter
Ions
lcsh:R
Biology and Life Sciences
Arrhythmias, Cardiac
biology.protein
lcsh:Q
Calcium
Reactive Oxygen Species
Oxidative stress
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 9
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- PloS one
- Accession number :
- edsair.doi.dedup.....5e12da5d02a5a467c395362f1646a82f