Key result
Selective inhibition of phospholipase C activity by U73122 in wild-type mice exacerbated adriamycin-induced cardiac dysfunction, resulting in decreased left ventricular ejection fraction.
Phospholipase C-delta1 is identified as a critical downstream target of TNF receptor signaling that protects against adriamycin-induced cardiotoxicity.
TNF receptor cytoprotection against adriamycin cardiomyopathy identifies candidate targets; leaves open functional validation before any clinical application.
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.
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Lien et al. (2006) studied Adriamycin-induced cardiac injury. Selective inhibition of phospholipase C activity by U73122 vs. Wild-type mice without inhibitor and double TNF receptor-deficient mice was evaluated on Cardiac function (left ventricular ejection fraction and fractional shortening). Selective inhibition of phospholipase C activity by U73122 in wild-type mice exacerbated adriamycin-induced cardiac dysfunction, resulting in decreased left ventricular ejection fraction.
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