The Central Role of Protein Kinase C Epsilon in Cyanide Cardiotoxicity and Its Treatment

Published on Sep 1, 2019in Toxicological Sciences3.703
· DOI :10.1093/TOXSCI/KFZ137
Joseph Y. Cheung69
Estimated H-index: 69
(TU: Temple University),
Salim Merali31
Estimated H-index: 31
(TU: Temple University)
+ 7 AuthorsPhilippe Haouzi23
Estimated H-index: 23
(PSU: Pennsylvania State University)
: In adult mouse myocytes, brief exposure to sodium cyanide (CN) in the presence of glucose does not decrease ATP levels, yet produces profound reduction in contractility, intracellular Ca2+ concentration ([Ca2+]i) transient and L-type Ca2+ current (ICa) amplitudes. We analyzed proteomes from myocytes exposed to CN, focusing on ionic currents associated with excitation-contraction coupling. CN induced phosphorylation of α1c subunit of L-type Ca2+ channel and α2 subunit of Na+-K+-ATPase. Methylene blue (MB), a CN antidote that we previously reported to ameliorate CN-induced reduction in contraction, [Ca2+]i transient and ICa amplitudes, was able to reverse this phosphorylation. CN decreased Na+-K+-ATPase current contributed by α2 but not α1 subunit, an effect that was also counteracted by MB. Peptide consensus sequences suggested CN-induced phosphorylation was mediated by protein kinase C epsilon (PKCe). Indeed, CN stimulated PKC kinase activity and induced PKCe membrane translocation, effects that were prevented by MB. Pre-treatment with myristoylated PKCe translocation activator or inhibitor peptides mimicked and inhibited the effects of CN on ICa and myocyte contraction, respectively. We conclude that CN activates PKCe, which phosphorylates L-type Ca2+ channel and Na+-K+-ATPase, resulting in depressed cardiac contractility. We hypothesize that this inhibition of ion fluxes represents a novel mechanism by which the cardiomyocyte reduces its ATP demand (decreased ion fluxes and contractility), diminishes ATP turnover and preserves cell viability. However, this cellular protective effect translates into life-threatening cardiogenic shock in vivo, thereby creating a profound disconnect between survival mechanisms at the cardiomyocyte level from those at the level of the whole organism.
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