Doxorubicin Selectively Inhibits Brain Versus Atrial Natriuretic Peptide Gene Expression in Cultured Neonatal Rat Myocytes

Chen, Songcang; Garami, Miklós; Gardner, David G.

doi:10.1161/01.hyp.34.6.1223

Cited by 36 publications

(25 citation statements)

References 37 publications

(45 reference statements)

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“…However, it was paradoxical that increasing DOX concentrations led to elevated ferritin protein expression, suggesting selective targeting of gene expression. This finding was surprising, but it was in accordance with previous studies demonstrating the effect of DOX at differentially targeting the expression of other genes (Ito et al, 1990;Chen et al, 1999). This selective activity of DOX has not been reported for genes involved or modulated by iron metabolism.…”

Section: Discussionsupporting

confidence: 89%

Iron Chelation by Clinically Relevant Anthracyclines: Alteration in Expression of Iron-Regulated Genes and Atypical Changes in Intracellular Iron Distribution and Trafficking

Šuták²,

Richardson³

2007

Mol Pharmacol

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Anthracyclines are effective anticancer agents. However, their use is limited by cardiotoxicity, an effect linked to their ability to chelate iron and to perturb iron metabolism (Mol Pharmacol 68:261-271, 2005). These effects on iron-trafficking remain poorly understood, but they are important to decipher because treatment for anthracycline cardiotoxicity uses the chelator, dexrazoxane. Incubation of cells with doxorubicin (DOX) upregulated mRNA levels of the iron-regulated genes transferrin receptor-1 (TfR1) and N-myc downstream-regulated gene-1 (Ndrg1). This effect was mediated by iron depletion, because it was reversed by adding iron and it was prevented by saturating the anthracycline metal binding site with iron. However, DOX did not act like a typical chelator, because it did not induce cellular iron mobilization. In the presence of DOX and 59 Fetransferrin, iron-trafficking studies demonstrated ferritin-59 Fe accumulation and decreased cytosolic-59 Fe incorporation. This could induce cytosolic iron deficiency and increase TfR1 and Ndrg1 mRNA. Up-regulation of TfR1 and Ndrg1 by DOX was independent of anthracycline-mediated radical generation and occurred via hypoxia-inducible factor-1␣-independent mechanisms. Despite increased TfR1 and Ndrg1 mRNA after DOX treatment, this agent decreased TfR1 and Ndrg1 protein expression. Hence, the effects of DOX on iron metabolism were complex because of its multiple effector mechanisms.

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Section: Discussionsupporting

confidence: 89%

Iron Chelation by Clinically Relevant Anthracyclines: Alteration in Expression of Iron-Regulated Genes and Atypical Changes in Intracellular Iron Distribution and Trafficking

Šuták²,

Richardson³

2007

Mol Pharmacol

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“…The different expression levels of Bcl-2 after DOX injection among the three kinds of mice may reflect the different degrees of cardiac impairments, which may be dependent on the different expression of cardiac genes after DOX injection. It has been reported that ANP and BNP are sensitive markers of cardiac impairments induced by DOX (26). In this study, DOX suppressed the transcription of ANP, BNP, CARP, and SERCA2 in non-TG mice.…”

Section: Discussionsupporting

confidence: 49%

Csx/Nkx2-5 Is Required for Homeostasis and Survival of Cardiac Myocytes in the Adult Heart

Toko¹,

Zhu²,

Takimoto³

et al. 2002

Journal of Biological Chemistry

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Csx/Nkx2-5, which is essential for cardiac development of the embryo, is abundantly expressed in the adult heart. We here examined the role of Csx/Nkx2-5 in the adult heart using two kinds of transgenic mice. Transgenic mice that overexpress a dominant negative mutant of Csx/Nkx2-5 (DN-TG mice) showed degeneration of cardiac myocytes and impairment of cardiac function. Doxorubicin induced more marked cardiac dysfunction in DN-TG mice and less in transgenic mice that overexpress wild type Csx/Nkx2-5 (WT-TG mice) compared with non-transgenic mice. Doxorubicin induced cardiomyocyte apoptosis, and the number of apoptotic cardiomyocytes was high in the order of DN-TG mice, non-transgenic mice, and WT-TG mice. Overexpression of the dominant negative mutant of Csx/Nkx2-5 induced apoptosis in cultured cardiomyocytes, while expression of wild type Csx/Nkx2-5 protected cardiomyocytes from doxorubicin-induced apoptotic death. These results suggest that Csx/Nkx2-5 plays a critical role in maintaining highly differentiated cardiac phenotype and in protecting the heart from stresses including doxorubicin.The cardiac homeobox gene Csx/Nkx2-5 starts to be expressed at embryonic day 7.5 in the heart primordia of mice (1, 2), and targeted disruption of murine Csx/Nkx2-5 results in embryonic lethality (3). Many mutations in human Csx/Nkx2-5 have been reported to cause a variety of congenital heart diseases and atrioventricular conduction delay (4, 5). These observations indicate that Csx/Nkx2-5 plays a critical role in cardiac morphogenesis and contributes to diverse cardiac developmental pathways at the embryonic stage.Knockout experiments have suggested that many genes such as Hand1, myocyte enhancer factor-2, atrial natriuretic peptide (ANP), 1 brain natriuretic peptide (BNP), cardiac ␣-actin, cardiac ankyrin repeat protein (CARP), N-myc, and MSX2 are genetically located downstream of Csx/Nkx2-5 at the embryonic stage (2, 6 -8). Although Csx/Nkx2-5 continues to be expressed in the adult heart (1, 2), the function of Csx/Nkx2-5 in the later stage of development is unknown because of embryonic lethality of null mutant mice (3, 8). In our recently generated transgenic mice that overexpress human Csx/Nkx2-5 (WT-TG mice), mRNA levels of many cardiac genes such as ANP, BNP, CARP, and sarcoplasmic reticulum calcium ATPase 2 (SERCA2) genes were up-regulated (9). These results suggest that Csx/Nkx2-5 regulates expression of cardiac-specific genes also in the adult heart. However, because there was no difference in phenotype between WT-TG and non-transgenic (non-TG) mice (9), the significance of these gene up-regulations remains unknown. Csx/Nkx2-5 itself is also differentially regulated by different stimuli. In response to hypertrophic stimuli such as isoproterenol, phenylephrine, and pressure overload, Csx/Nkx2-5 is upregulated (10, 11), whereas it is down-regulated by treatment with doxorubicin (DOX) (12). These results suggest that Csx/ Nkx2-5 has certain roles in the adult heart. In this study, we generated transgenic mice that over...

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“…Our laboratory recently found that forced expression of GATA-4 enhances the expression of Bcl-x L in cardiac myocytes (Kitta et al, 2003). Anthracyclines also suppress expression of several GATA-regulated cardiac genes such as cardiac adriamycin-responsive protein (Jeyaseelan et al, 1997), brain and atrial natriuretic proteins (Chen et al, 1999), ␣-myosin heavy chain (Saadane et al, 1999), and calsequestrin (Arai et al, 1998). The present study suggests that modulating the levels of GATA factors may be an effective therapeutic strategy against anthracycline-induced cardiotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…Functionally relevant GATA-binding sites have been identified in numerous cardiac transcriptional regulatory regions (Charron and Nemer, 1999;Molkentin, 2000). Anthracyclines have been shown to suppress expression of several GATA-regulated genes, including cardiac adriamycin-responsive protein (Jeyaseelan et al, 1997), brain, and atrial natriuretic proteins (Chen et al, 1999), ␣-myosin heavy chain (Saadane et al, 1999) and calsequestrin (Arai et al, 1998). However, the effects of anthracyclines on GATA transcription factors have not been studied.…”

mentioning

confidence: 99%

Anthracycline-Induced Suppression of GATA-4 Transcription Factor: Implication in the Regulation of Cardiac Myocyte Apoptosis

et al. 2003

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Doxorubicin Selectively Inhibits Brain Versus Atrial Natriuretic Peptide Gene Expression in Cultured Neonatal Rat Myocytes

Cited by 36 publications

References 37 publications

Iron Chelation by Clinically Relevant Anthracyclines: Alteration in Expression of Iron-Regulated Genes and Atypical Changes in Intracellular Iron Distribution and Trafficking

Iron Chelation by Clinically Relevant Anthracyclines: Alteration in Expression of Iron-Regulated Genes and Atypical Changes in Intracellular Iron Distribution and Trafficking

Csx/Nkx2-5 Is Required for Homeostasis and Survival of Cardiac Myocytes in the Adult Heart

Anthracycline-Induced Suppression of GATA-4 Transcription Factor: Implication in the Regulation of Cardiac Myocyte Apoptosis

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