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Antioxid Redox Signal. 2013 Mar 20;18(9):1063-77. doi: 10.1089/ars.2012.4818. Epub 2012 Oct 3.

Redox regulation of sodium and calcium handling.

Author information

1
Abt. Kardiologie und Pneumologie/Herzzentrum, Deutsches Zentrum für Herzkreislaufforschung, Georg-August-Universität, Göttingen, Germany.

Abstract

SIGNIFICANCE:

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.

RECENT ADVANCES:

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.

CRITICAL ISSUES:

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.

FUTURE DIRECTIONS:

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.

PMID:
22900788
PMCID:
PMC3567778
DOI:
10.1089/ars.2012.4818
[Indexed for MEDLINE]
Free PMC Article

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