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Title: Glucocorticoid induced leucine zipper inhibits apoptosis of cardiomyocytes by doxorubicin.

Authors: Aguilar, David; Strom, Joshua; Chen, Qin M

Published In Toxicol Appl Pharmacol, (2014 Apr 01)

Abstract: Doxorubicin (Dox) is an indispensable chemotherapeutic agent for the treatment of various forms of neoplasia such as lung, breast, ovarian, and bladder cancers. Cardiotoxicity is a major concern for patients receiving Dox therapy. Previous work from our laboratory indicated that glucocorticoids (GCs) alleviate Dox-induced apoptosis in cardiomyocytes. Here we have found glucocorticoid-induced leucine zipper (GILZ) to be a mediator of GC-induced cytoprotection. GILZ was found to be induced in cardiomyocytes by GC treatment. Knocking down of GILZ using siRNA resulted in cancelation of GC-induced cytoprotection against apoptosis by Dox treatment. Overexpressing GILZ by transfection was able to protect cells from apoptosis induced by Dox as measured by caspase activation, Annexin V binding and morphologic changes. Western blot analyses indicate that GILZ overexpression prevented cytochrome c release from mitochondria and cleavage of caspase-3. When bcl-2 family proteins were examined, we found that GILZ overexpression causes induction of the pro-survival protein Bcl-xL. Since siRNA against Bcl-xL reverses GC induced cytoprotection, Bcl-xL induction represents an important event in GILZ-induced cytoprotection. Our data suggest that GILZ functions as a cytoprotective gene in cardiomyocytes.

PubMed ID: 24480152 Exiting the NIEHS site

MeSH Terms: Animals; Antibiotics, Antineoplastic/adverse effects; Apoptosis/drug effects*; Cardiotonic Agents/antagonists & inhibitors; Cardiotonic Agents/pharmacology*; Cardiotoxins/adverse effects; Cardiotoxins/antagonists & inhibitors*; Cell Line; Cell Survival/drug effects; Corticosterone/antagonists & inhibitors; Corticosterone/pharmacology; Doxorubicin/adverse effects; Doxorubicin/antagonists & inhibitors*; Glucocorticoids/antagonists & inhibitors; Glucocorticoids/pharmacology*; Mice; Myocytes, Cardiac/drug effects*; Myocytes, Cardiac/metabolism; RNA Interference; RNA, Small Interfering; Rats; Recombinant Proteins/chemistry; Recombinant Proteins/metabolism; Transcription Factors/agonists; Transcription Factors/antagonists & inhibitors; Transcription Factors/genetics; Transcription Factors/metabolism*; Up-Regulation/drug effects; bcl-X Protein/agonists; bcl-X Protein/antagonists & inhibitors; bcl-X Protein/genetics; bcl-X Protein/metabolism

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