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Modification of Ca(2+)-handling in cardiomyocytes by redox sensitive mechanisms in response to ouabain

Harjot K Saini-Chohan1, Larry Hryshko, Yan-Jun Xu

  • 1Institute of Cardiovascular Sciences, St. Boniface Hospital Research and Department of Physiology, Faculty of Medicine, University of Manitoba, 351 Tache Avenue, Winnipeg, MB R2H 2A6, Canada.

Canadian Journal of Physiology and Pharmacology
|February 2, 2013
PubMed

Insights

Ouabain increases intracellular calcium in heart cells by producing oxyradicals. Antioxidants and specific protein kinase inhibitors modulate these calcium changes, revealing redox-sensitive signaling pathways in cardiomyocytes.

Area of Science:

  • Cardiology
  • Cell Signaling
  • Biochemistry

Background:

  • Ouabain is a cardiac glycoside known to affect cardiomyocyte function.
  • Redox signaling pathways play a crucial role in cellular responses to various stimuli.
  • Intracellular calcium ([Ca(2+)](i)) regulation is vital for cardiac contractility.

Purpose of the Study:

  • To investigate the role of redox-sensitive signal transduction mechanisms in mediating ouabain's effects on [Ca(2+)](i) in adult rat cardiomyocytes.
  • To elucidate the involvement of specific protein kinases and oxyradical production in ouabain-induced calcium changes.

Main Methods:

  • Adult rat cardiomyocytes were incubated with ouabain, antioxidants, or protein kinase inhibitors.
  • Changes in intracellular calcium ([Ca(2+)](i)) were monitored using fura-2 fluorescence.
  • Oxyradical production was assessed in response to ouabain treatment.

Main Results:

  • Ouabain increased basal [Ca(2+)](i), augmented KCl-induced [Ca(2+)](i) increases, and promoted oxyradical production.
  • Antioxidants (superoxide dismutase plus catalase, N-acetyl-L-cysteine, N-(2-mercaptoproprionyl)glycine) attenuated ouabain's effects.
  • Inhibitors of MAP kinase (PD98059) depressed, while tyrosine kinase and PI3 kinase inhibitors (tyrphostin, genistein, Wortmannin, LV294002) enhanced ouabain-induced [Ca(2+)](i) increases.
  • Protein kinase C (PKC) inhibitors (calphostin, bisindolylmalaimide) augmented, while PKC stimulation (phorbol 12-myristate 13-acetate) depressed ouabain's action.

Conclusions:

  • Ouabain-induced inhibition of Na(+)-K(+) ATPase alters cardiomyocyte redox status via oxyradical production.
  • Redox-sensitive signal transduction pathways involving various protein kinases modulate ouabain's impact on [Ca(2+)](i).
  • These mechanisms fine-tune Ca(2+) handling sites in cardiomyocytes, determining the net increase in [Ca(2+)](i).

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