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Lien, Y.C. et al.

Phospholipase C-delta1 is a critical target for tumor necrosis factor receptor-mediated protection against adriamycin-induced cardiac injury.

The clinical application of adriamycin, an exceptionally good chemotherapeutic agent, is limited by its dose-related cardiomyopathy. Our recent study showed that tumor necrosis factor-alpha ( TNF-alpha) receptors mediated cytoprotective signaling against adriamycin-induced mitochondrial injury and cardiomyocyte apoptosis. In the present study, we investigated the potential targets of TNF receptor-mediated cytoprotective signaling by global genome microarray analysis using wild-type and TNF receptor-deficient mice. Microarray analysis revealed that adriamycin treatment induced the down-regulation of several mitochondrial functions and energy production-related genes in double TNF receptor-deficient mice, notably, phospholipase C-delta1, a protein involved in fatty acid metabolism and calcium regulation. The role of phospholipase C-delta1 in TNF receptor-mediated cardioprotection against adriamycin-induced injury was evaluated by measuring changes in cardiac function using high-frequency ultrasound biomicroscopy. Selective inhibition of phospholipase C activity in wild-type mice by its inhibitor, U73122, exacerbated adriamycin-induced cardiac dysfunction. Inhibition of phospholipase C-delta1 resulted in the significant decrease of left ventricular ejection fraction and fractional shortening, and the decreased levels were similar to those observed in adriamycin-treated double TNF receptor-deficient mice. The data derived from the global genome analysis identified phospholipase C-delta1 as an important target for TNF receptors and revealed the critical role of TNF receptor signaling in the protection against adriamycin-induced cardiotoxicity.[1]

References

Phospholipase C-delta1 is a critical target for tumor necrosis factor receptor-mediated protection against adriamycin-induced cardiac injury. Lien, Y.C., Noel, T., Liu, H., Stromberg, A.J., Chen, K.C., St Clair, D.K. Cancer Res. (2006) [Pubmed]

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