Redox regulation of sodium and calcium handling.
CONCLUSIONS
In heart failure (HF), contractile dysfunction and arrhythmias result from disturbed intracellular Ca handling. Activated stress kinases like cAMP-dependent protein kinase A (PKA), protein kinase C (PKC), and Ca/calmodulin-dependent protein kinase II (CaMKII), which are known to influence many Ca-regulatory proteins, are mechanistically involved.


BACKGROUND
Beside classical activation pathways, it is becoming increasingly evident that reactive oxygen species (ROS) can directly oxidize these kinases, leading to alternative activation. Since HF is associated with increased ROS generation, ROS-activated serine/threonine kinases may play a crucial role in the disturbance of cellular Ca homeostasis. Many of the previously described ROS effects on ion channels and transporters are possibly mediated by these stress kinases. For instance, ROS have been shown to oxidize and activate CaMKII, thereby increasing Na influx through voltage-gated Na channels, which can lead to intracellular Na accumulation and action potential prolongation. Consequently, Ca entry via activated NCX is favored, which together with ROS-induced dysfunction of the sarcoplasmic reticulum can lead to dramatic intracellular Ca accumulation, diminished contractility, and arrhythmias.


RESULTS
While low amounts of ROS may regulate kinase activity, excessive uncontrolled ROS production may lead to direct redox modification of Ca handling proteins. Therefore, depending on the source and amount of ROS generated, ROS could have very different effects on Ca-handling proteins.


CONCLUSIONS
The discrimination between fine-tuned ROS signaling and unspecific ROS damage may be crucial for the understanding of heart failure development and important for the investigation of targeted treatment strategies.
Abt. Kardiologie und Pneumologie/Herzzentrum, Deutsches Zentrum für Herzkreislaufforschung, Georg-August-Universität, Göttingen, Germany.
Stefan
S
Wagner
Adam G
AG
Rokita
Mark E
ME
Anderson
Lars S
LS
Maier
D001145:Arrhythmias, Cardiac / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D017136:Ion Transport / Q000502:physiology; D008929:Mitochondria, Heart / Q000378:metabolism; D008955:Models, Cardiovascular; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D015220:Calcium Channels; D017382:Reactive Oxygen Species; D015222:Sodium Channels; D013481:Superoxides; D012964:Sodium; D019255:NADPH Oxidases; D011494:Protein Kinases; D002118:Calcium