Inhibiting Na+/K+ ATPase can impair mitochondrial energetics and induce abnormal Ca2+ cycling and automaticity in guinea pig cardiomyocytes.
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.
Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Qince
Q
Li
Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Steven M
SM
Pogwizd
Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Sumanth D
SD
Prabhu
Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Lufang
L
Zhou
D000200:Action Potentials; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001145:Arrhythmias, Cardiac / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D003198:Computer Simulation; D006168:Guinea Pigs; D006706:Homeostasis; D007477:Ions; D008564:Membrane Potentials; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology*; D010085:Oxidative Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
D000975:Antioxidants; D007477:Ions; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium