Glucocorticoid Induced Leucine Zipper inhibits apoptosis of cardiomyocytes by doxorubicin

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.

Glucocorticoid-Induced Leucine Zipper Protects the Retina From Light-Induced Retinal Degeneration by Inducing Bcl-xL in Rats

“…The relationship between GILZ and Bcl-xL was reported previously, and the antiapoptotic function of GILZ is mediated by the upregulation of Bcl-xL. 12,29 In the present study, GILZ overexpression upregulated retinal Bcl-xL, whereas GILZ silencing enhanced the decrease in retinal Bcl-xL at the mRNA and protein levels. These results indicate that the antiapoptotic effects of GILZ in the retina may be mediated by the maintenance of retinal Bcl-xL levels.…”

“…12 In cardiomyocytes, GILZ overexpression protects cells from apoptosis by upregulating Bcl-xL expression, preventing cytochrome c release from mitochondria and caspase-3 cleavage. 13 Bruscoli et al 14…”

Glucocorticoid-Induced Leucine Zipper Promotes Neutrophil and T-Cell Polarization with Protective Effects in Acute Kidney Injury

“…These observation are consistent with those of our recent study , whereby intramyocardial treatment with GILZ-overexpressing mesenchymal stem cells exerted significant cardioprotection. Others (Aguilar et al, 2014) have shown that GILZ overexpression protects against doxorubicin-induced cardiomyopathy, as exemplified by the induction of prosurvival protein Bcl-xL, the prevention of mitochondrial release of cytochrome c, and the cleavage of caspase-3. Similarly, GILZ overexpression protects against endoplasmic reticulum stress-mediated cell death, likely via the stimulation of mitochondrial oxidative phosphorylation (André et al, 2016).…”

Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer

“…2007 ). As such, GR-target gene GILZ was shown to induce Bcl-xL expression thereby protecting cardiomyocytes for doxorubicin cytotoxicity ( Aguilar et al . 2014 ).…”