Expression of Glucocorticoid-Induced Leucine Zipper (GILZ) in Cardiomyocytes

Strom, Joshua; Xu, Beibei; Kappeler, Kyle V.; Chen, Qin M.

doi:10.1007/s12012-012-9188-5

Cited by 11 publications

(14 citation statements)

References 49 publications

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“…Furthermore, GILZ mRNA expression can be used as a marker for in vivo GC action. The expression of GILZ at both the mRNA and protein levels in various human cell lines and some tissues was previously documented (Cannarile et al 2001;Berrebi et al 2003;Eddleston et al 2007;Aguilar et al 2013). Here, we demonstrate constitutive GILZ expression in all tissues examined.…”

Section: Discussionsupporting

confidence: 76%

“…GILZ is expressed in human airway epithelial cells where they significantly inhibited IL-1b and LPS-induced activation of NFjB (Eddleston et al 2007). GC-enhanced GILZ expression in mouse heart and in primary cultured rat cardiomyocytes, even at doses as low as 0.1 lmol/L-DEX (Aguilar et al 2013). Furthermore, GILZ mediated the anti-myogenic effect of GC in myoblasts by inhibition of myoblast differentiation and their maturation into myotubes (Bruscoli et al 2010).…”

Section: Discussionmentioning

confidence: 95%

“…GC‐enhanced GILZ expression in mouse heart and in primary cultured rat cardiomyocytes, even at doses as low as 0.1 μ mol/L‐DEX (Aguilar et al. ). Furthermore, GILZ mediated the anti‐myogenic effect of GC in myoblasts by inhibition of myoblast differentiation and their maturation into myotubes (Bruscoli et al.…”

Section: Discussionmentioning

confidence: 99%

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Quantitative tissue-specific dynamics of in vivo GILZ mRNA expression and regulation by endogenous and exogenous glucocorticoids

et al. 2015

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Glucocorticoids (GC) are steroid hormones, which regulate metabolism and immune function. Synthetic GCs, or corticosteroids (CS), have appreciable clinical utility via their ability to suppress inflammation in immune-mediated diseases like asthma and rheumatoid arthritis. Recent work has provided insight to novel GC-induced genes that mediate their anti-inflammatory effects, including glucocorticoid-induced leucine zipper (GILZ). Since GILZ comprises an important part of GC action, its regulation by both drug and hormone will influence CS therapy. In addition, GILZ expression is often employed as a biomarker of GC action, which requires judicious selection of sampling time. Understanding the in vivo regulation of GILZ mRNA expression over time will provide insight into both the physiological regulation of GILZ by endogenous GC and the dynamics of its enhancement by CS. A highly quantitative qRT-PCR assay was developed for measuring GILZ mRNA expression in tissues obtained from normal and CS-treated rats. This assay was applied to measure GILZ mRNA expression in eight tissues; to determine its endogenous regulation over time; and to characterize its dynamics in adipose tissue, muscle, and liver following treatment with CS. We demonstrate that GILZ mRNA is expressed in several tissues. GILZ mRNA expression in adipose tissue displayed a robust circadian rhythm that was entrained with the circadian oscillation of endogenous corticosterone; and is strongly enhanced by acute and chronic dosing. Single dosing also enhanced GILZ mRNA in muscle and liver, but the dynamics varied. In conclusion, GILZ is widely expressed in the rat and highly regulated by endogenous and exogenous GCs.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 95%

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Quantitative tissue-specific dynamics of in vivo GILZ mRNA expression and regulation by endogenous and exogenous glucocorticoids

et al. 2015

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“…A recent study from our laboratory indicates that corticosteroids induce GILZ in the mouse myocardium and H9c2 cells resemble primary cultured rat cardiomyocytes in regards to GILZ expression by GCs, thereby making H9c2 cells a serviceable in vitro model for studying the function of GILZ in cardiomyocytes (Aguilar et al , 2013). We investigated the role of GILZ in GC-induced cytoprotection by knocking down GILZ expression with siRNA.…”

Section: Resultsmentioning

confidence: 99%

“…Since GCs elevated Bcl-xL mRNA and protein levels, but GILZ overexpression was only able to affect Bcl-xL protein levels, it would suggest that GILZ may play only a partial role in GC-induced protection against Dox. However, GC induces prolonged elevation of GILZ (Aguilar et al , 2013) and knockdown of GILZ with siRNA completely abolished GC-induced inhibition of caspase activation comparable to knockdown of Bcl-xL. This argues that maintenance of Bcl-xL protein elevation by GILZ is just as important as transcriptional activation of Bcl-xL for cell survival.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid Induced Leucine Zipper inhibits apoptosis of cardiomyocytes by doxorubicin

Aguilar

Strom

Chen

2014

Toxicology and Applied Pharmacology

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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.

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Vitamin D interferes with glucocorticoid responsiveness in human peripheral blood mononuclear target cells

Kassi

Nasiri-Ansari

Spilioti

et al. 2016

Cell. Mol. Life Sci.

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Glucocorticoids (GCs) are widely used in the treatment of inflammatory and autoimmune diseases; however, patients are often resistant to GC effects. Current studies indicate that vitamin D reduces the risk or modifies the course of autoimmune diseases posing vitamin D supplementation as a prevention or therapeutic option. Herein, we investigated whether vitamin D can modify the response to GCs at the molecular level. To this end, peripheral blood mononuclear cells (PBMCs) were isolated from healthy vitamin D-deficient women and incubated with either the active metabolite 1,25(OH)D (VitD) for 11 days or dexamethasone (Dex) for the last 2 days in the presence or absence of VitD. Ex vivo GC sensitivity was assessed by the expression of the glucocorticoid receptor (GR) responsive gene GILZ with RT-PCR. Long-term incubation of PBMCs with VitD significantly decreased the Dex-induced augmentation of GILZ expression. Since the intracellular concentration of GR and the GR nuclear translocation are critical determinants of GC sensitivity, we next evaluated the effect of VitD on these factors. RT-PCR and western-blot analysis revealed that VitD reduced the expression of GR. This effect was abolished by the HDAC-specific inhibitor trichostatin A, implying that HDAC was implicated in this effect. Moreover, NCoR1 mRNA was significantly decreased upon treatment with VitD either alone or as pre-treatment to Dex, suggesting that a possible increase in expression of this co-repressor was not involved. In addition, immunofluorescence analysis showed that VitD hindered the Dex-induced GRα nuclear translocation, an effect verified by subcellular fractionation and western-blot experiments. To further explore the underpinning mechanism, we examined the potential of VitD to: (1) strengthen the FK506-binding protein 5 (FKBP5) negative feedback loop and (2) modify the phosphorylation status of GR. Remarkably, VitD decreased FKBP5 expression and decreased phosphorylation at Ser211, while enhancing phosphorylation of GR at Ser203. Overall, VitD decreases the ex vivo GC sensitivity and this effect is, at least in part, attributed both to decrease of GR expression owing to a mechanism that engages HDAC and inhibition of GR translocation to nucleus via differential modulation of the phosphorylation state of GR. Our study provides, for the first time, evidence that long-term action of VitD induces GC resistance in PBMCs from healthy volunteers and offers a possible mechanistic basis for VitD-triggered attenuation of GC effects.

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Expression of Glucocorticoid-Induced Leucine Zipper (GILZ) in Cardiomyocytes

Cited by 11 publications

References 49 publications

Quantitative tissue-specific dynamics of in vivo GILZ mRNA expression and regulation by endogenous and exogenous glucocorticoids

Quantitative tissue-specific dynamics of in vivo GILZ mRNA expression and regulation by endogenous and exogenous glucocorticoids

Glucocorticoid Induced Leucine Zipper inhibits apoptosis of cardiomyocytes by doxorubicin

Vitamin D interferes with glucocorticoid responsiveness in human peripheral blood mononuclear target cells

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