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Inhibition of phospholipase C-₁ augments the decrease in cardiomyocyte viability by H₂O₂

¹Department of Human Nutritional Sciences, Faculty of Human Ecology, ²Department of Physiology, Faculty of Medicine, and ³Department of Human Anatomy and Cell Science, University of Manitoba, and Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, Winnipeg, Canada

Submitted 14 November 2005 ; accepted in final form 23 February 2006

The present study was conducted to examine the role of a major cardiac phospholipase C (PLC) isozyme, PLC-₁, in cardiomyocytes during oxidative stress. Left ventricular cardiomyocytes were isolated by collagenase digestion from adult male Sprague-Dawley rats (250–300 g) and treated with 20, 50, and 100 µM H₂O₂ for 15 min. A concentration-dependent (up to 50 µM) increase in the mRNA level and membrane protein content of PLC-₁ was observed with H₂O₂ treatment. Furthermore, PLC-₁ was activated in response to H₂O₂, as revealed by an increase in the phosphorylation of its tyrosine residues. There was a marked increase in the phosphorylation of the antiapoptotic protein Bcl-2 by H₂O₂; this change was attenuated by a PLC inhibitor, U-73122. Although both protein kinase C (PKC)- and - protein contents were increased in the cardiomyocyte membrane fraction in response to H₂O₂, PKC- activation, unlike PKC-, was attenuated by U-73122 (2 µM). Inhibition of PKC- with inhibitory peptide (0.1 µM) prevented Bcl-2 phosphorylation. Moreover, different concentrations (0.05, 0.1, and 0.2 µM) of this peptide augmented the decrease in cardiomyocyte viability in response to H₂O₂. In addition, a decrease in cardiomyocyte viability, as assessed by trypan blue exclusion, due to H₂O₂ was also seen when cells were pretreated with U-73122 and was as a result of increased apoptosis. It is therefore suggested that PLC-₁ may play a role in cardiomyocyte survival during oxidative stress via PKC- and phosphorylation of Bcl-2.

cardiomyocyte viability; phospholipase C; signal transduction

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