This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lien, Y.-C. Articles by St. Clair, D. K. Search for Related Content PubMed PubMed Citation Articles by Lien, Y.-C. Articles by St. Clair, D. K.

Phospholipase C-1 Is a Critical Target for Tumor Necrosis Factor Receptor–Mediated Protection against Adriamycin-Induced Cardiac Injury

¹ Graduate Center for Toxicology, Departments of ² Statistics and ³ Molecular and Biomedical Pharmacology, and ⁴ UK Microarray Core Facility, University of Kentucky, Lexington, Kentucky

Requests for reprints: Daret K. St. Clair, Graduate Center for Toxicology, 454 Health Sciences Research Building, University of Kentucky, Lexington, KY 40536. Phone: 859-257-3956; Fax: 859-323-1059; E-mail: dstcl00{at}uky.edu.

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- (TNF-) 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-1, a protein involved in fatty acid metabolism and calcium regulation. The role of phospholipase C-1 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-1 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-1 as an important target for TNF receptors and revealed the critical role of TNF receptor signaling in the protection against adriamycin-induced cardiotoxicity. (Cancer Res 2006; 66(8): 4329-38)

This article has been cited by other articles:

				Y. Chen, P. Jungsuwadee, M. Vore, D. A. Butterfield, and D. K. St. Clair Collateral Damage in Cancer Chemotherapy: Oxidative Stress in Nontargeted Tissues Mol. Interv., June 1, 2007; 7(3): 147 - 156. [Abstract] [Full Text] [PDF]