Ouabain triggers preconditioning through activation of the Na+,K+-ATPase signaling cascade in rat hearts

doi:10.1016/j.cardiores.2006.11.003

Cardiovascular Research 2007 73(3):488-496; doi:10.1016/j.cardiores.2006.11.003

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Ouabain triggers preconditioning through activation of the Na⁺,K⁺-ATPase signaling cascade in rat hearts

Sandrine V. Pierre^a, Changjun Yang^a, Zhaokan Yuan^a, Jennifer Seminerio^a, Christian Mouas^b, Keith D. Garlid^c, Pierre Dos-Santos^d and Zijian Xie^a^,*

^aDepartment of Physiology, Pharmacology, Metabolism and Cardiovascular Sciences, Medical University of Ohio, 3035 Arlington Avenue, Toledo, OH 43614-5804, United States
^bInserm U689, Centre de Cardiologie vasculaire de Lariboisiere, Paris, France
^cDepartment of Biology, Portland State University, Portland, Oregon, United States
^dInserm U.441, Avenue du Haut Leveque, Pessac, France

^* Corresponding author. Tel.: +1 419 383 4182; fax: +1 419 383 2871. Email address: zxie{at}meduohio.edu

Objective: Because ouabain activates several pathways that arecritical to cardioprotective mechanisms such as ischemic preconditioning,we tested if this digitalis compound could protect the heartagainst ischemia–reperfusion injury through activationof the Na⁺,K⁺-ATPase/c-Src receptor complex.

Methods and results: In Langendorff-perfused rat hearts, a short(4 min) administration of ouabain 10 µM followedby an 8-minute washout before 30 min of global ischemiaand reperfusion improved cardiac function, decreased lactatedehydrogenase release and reduced infarct size by 40%. Westernblot analysis revealed that ouabain activated the cardioprotectivephospholipase C ${gamma}$ 1/protein kinase C ${varepsilon}$ (PLC- ${gamma}$ 1/PKC ${varepsilon}$ ) pathway. Pre-treatmentof the hearts with the Src kinase family inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolol[3,4-d]pyrimidine(PP2) blocked not only ouabain-induced activation of PLC- ${gamma}$ 1/PKC ${varepsilon}$ pathway, but also cardiac protection. This protection was alsoblocked by a PKC ${varepsilon}$ translocation inhibitor peptide (PKC ${varepsilon}$ TIP).

Conclusion: Short exposure to a low concentration of ouabainprotects the heart against ischemia/reperfusion injury. Thiseffect of ouabain on the heart is most likely due to the activationof the Na⁺,K⁺-ATPase/c-Src receptor complex and subsequent stimulationof key mediators of preconditioning, namely PLC- ${gamma}$ 1 and PKC ${varepsilon}$ .

KEYWORDS Ischemia; Reperfusion; Signal transduction; Na/K-pump

Time for primary review 15 days

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