Phospholipase C-δ1 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-A (TNF-A) 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 wildtype and TNF receptor-deficient mice. Microarray analysis revealed that adriamycin treatment induced the downregulation of several mitochondrial functions and energy production-related genes in double TNF receptor-deficient mice, notably, phospholipase C-D1, a protein involved in fatty acid metabolism and calcium regulation. The role of phospholipase C-D1 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-D1 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-D1 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)

PLCδ1 Protein Rescues Ischemia-reperfused Heart by the Regulation of Calcium Homeostasis

“…26 This result correlates with our data because adriamycin is known to induce cardiac apoptosis due to oxidative stress and calcium overload by mitochondrial dysfunction. 27 Therefore, previous studies support our hypothesis that PLCδ1 has a therapeutic potential for ischemic heart disease.…”

Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury

“…Upon the ADR-induced oxidative insult, transcription of protective genes [41,42] requires the acetylation of histones (H2A,H2B, H3, and H4) and transcription factors, such as RelA, Sp1, and p53 [22,24,43,44]. HDAC inhibitors (HDACIs) may sustain the activation of target genes via inhibition of HDACs [21,24].…”

Persistent Alterations to the Gene Expression Profile of the Heart Subsequent to Chronic Doxorubicin Treatment

“…In studying the mechanism of DOX cardiotoxicity, determining global alterations in gene expression would be beneficial to characterizing prominent long-term gene targets of the drug in cardiac tissue that may define the toxicological mechanism. Several studies undertaking the task of using microarrays to evaluate gene expression changes associated with DOX have identified mitochondria and metabolism genes as prominent targets, however the models used have employed dosing regimens that are supraclinical and/ or do not reflect the clinical situation in which cardiotoxicity is often noted beyond the time of drug exposure [8,15,16].…”