| First Author | Lien YC | Year | 2006 |
| Journal | Cancer Res | Volume | 66 |
| Issue | 8 | Pages | 4329-38 |
| PubMed ID | 16618758 | Mgi Jnum | J:108315 |
| Mgi Id | MGI:3623686 | Doi | 10.1158/0008-5472.CAN-05-3424 |
| Citation | Lien YC, et al. (2006) Phospholipase C-delta1 is a critical target for tumor necrosis factor receptor-mediated protection against adriamycin-induced cardiac injury. Cancer Res 66(8):4329-38 |
| abstractText | 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. |
