title: Phospholipase C-delta1 is a critical target for tumor necrosis factor receptor-mediated protection against adriamycin-induced cardiac injury.
abstract: 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.
authors.affiliation: Graduate Center for Toxicology, Department of Statistics, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Yu-Chin
authors.initials: YC
authors.lastname: Lien
authors.forename: Teresa
authors.initials: T
authors.lastname: Noel
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Stromberg
authors.forename: Kuey-Chu
authors.initials: KC
authors.lastname: Chen
authors.forename: Daret K
authors.initials: DK
authors.lastname: St Clair
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity*; D004734:Energy Metabolism / Q000235:genetics; D004963:Estrenes / Q000494:pharmacology; D006331:Heart Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D054803:Phospholipase C delta; D011760:Pyrrolidinones / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*
chemical_list: D004963:Estrenes; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D018124:Receptors, Tumor Necrosis Factor; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D004317:Doxorubicin; D010738:Type C Phospholipases; D054803:Phospholipase C delta; C518025:Plcd1 protein, mouse