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

Joseph Y. Cheung, Salim Merali, Jufang Wang, Xue Qian Zhang, Jianliang Song, Carmen Merali, Dhanendra Tomar, Hanning You, Annick Judenherc-Haouzi, Philippe Haouzi

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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 (PKCϵ). Indeed, CN stimulated PKC kinase activity and induced PKCϵ membrane translocation, effects that were prevented by MB. Pretreatment with myristoylated PKCϵ translocation activator or inhibitor peptides mimicked and inhibited the effects of CN on ICa and myocyte contraction, respectively. We conclude that CN activates PKCϵ, 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.

Original languageEnglish (US)
Pages (from-to)247-257
Number of pages11
JournalToxicological Sciences
Volume171
Issue number1
DOIs
StatePublished - Sep 1 2019

All Science Journal Classification (ASJC) codes

  • Toxicology

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