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

Kim, Yuri; Guo, AL; Kitta, Kazumi; Fitch, Sarah N.; Ikeda, Takayuki; Ihara, Yoshiharu; Simon, Amy; Evans, Todd; Suzuki, Yuichiro

doi:10.1124/mol.63.2.368

Cited by 170 publications

(128 citation statements)

References 38 publications

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“…Few prior studies on the development of DOX cardiomyopathy and the role of cardiomyocyte apoptosis have focused on the intrinsic pathway (7,18,26). Although we found evidence of both apoptosis and necrosis, this is not uncommon with initiation of intrinsic apoptosis.…”

Section: Discussioncontrasting

confidence: 48%

“…GATA-4 is inactivated in DOX cardiomyopathy, and GATA-4 overexpression protects against DOX-induced apoptosis (26,27), demonstrating a prosurvival function. We too have demonstrated that DOX interferes with GATA-4 DNA binding but also that CO restores cardiac GATA-4 activity, alone as well as after DOX, thereby connecting it directly to the GATA-4 antiatrophic effect.…”

Section: Discussionmentioning

confidence: 99%

“…Cardiac sarcomere protein expression is regulated in part by GATA family transcription factors (24,25), and DOX interferes with GATA-DNA binding activity (26,27). GATA binding activation was analyzed by EMSA in cardiomyocyte nucleoprotein, and gel supershifts showed the active protein in mouse heart to be mostly GATA-4.…”

Section: Figurementioning

confidence: 99%

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The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy

Suliman¹,

Carraway²,

Ali³

et al. 2007

J. Clin. Invest.

178

243

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The clinical utility of anthracycline anticancer agents, especially doxorubicin, is limited by a progressive toxic cardiomyopathy linked to mitochondrial damage and cardiomyocyte apoptosis. Here we demonstrate that the post-doxorubicin mouse heart fails to upregulate the nuclear program for mitochondrial biogenesis and its associated intrinsic antiapoptosis proteins, leading to severe mitochondrial DNA (mtDNA) depletion, sarcomere destruction, apoptosis, necrosis, and excessive wall stress and fibrosis. Furthermore, we exploited recent evidence that mitochondrial biogenesis is regulated by the CO/heme oxygenase (CO/HO) system to ameliorate doxorubicin cardiomyopathy in mice. We found that the myocardial pathology was averted by periodic CO inhalation, which restored mitochondrial biogenesis and circumvented intrinsic apoptosis through caspase-3 and apoptosis-inducing factor. Moreover, CO simultaneously reversed doxorubicin-induced loss of DNA binding by GATA-4 and restored critical sarcomeric proteins. In isolated rat cardiac cells, HO-1 enzyme overexpression prevented doxorubicin-induced mtDNA depletion and apoptosis via activation of Akt1/PKB and guanylate cyclase, while HO-1 gene silencing exacerbated doxorubicin-induced mtDNA depletion and apoptosis. Thus doxorubicin disrupts cardiac mitochondrial biogenesis, which promotes intrinsic apoptosis, while CO/HO promotes mitochondrial biogenesis and opposes apoptosis, forestalling fibrosis and cardiomyopathy. These findings imply that the therapeutic index of anthracycline cancer chemotherapeutics can be improved by the protection of cardiac mitochondrial biogenesis.

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Section: Discussioncontrasting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy

Suliman¹,

Carraway²,

Ali³

et al. 2007

J. Clin. Invest.

178

243

View full text Add to dashboard Cite

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“…26,27 We found myocardial levels of GATA-4 to be significantly reduced by DOX ( Figure 3), confirming earlier reports. 22,23 We also found that this reduction was partially but significantly restored by G-CSF treatment ( Figure 5). Likewise, levels of three sarcomeric proteins, MHC, troponin I and desmin, were significantly reduced by DOX, and this inhibitory effect was also significantly reversed by G-CSF.…”

Section: Effects Of Prophylactic Use Of G-csf On Dox-induced Cardiomymentioning

confidence: 48%

“…22,23 To detect apoptosis, the in situ nick end-labeling (TUNEL) assay was carried out in sections using an ApopTag kit (Intergene) principally according to the supplier's instructions. Mouse mammary tissue served as a positive control.…”

Section: Cell Death Assaysmentioning

confidence: 99%

Granulocyte colony-stimulating factor improves left ventricular function of doxorubicin-induced cardiomyopathy

Takemura

et al. 2007

Laboratory Investigation

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It is not well-known yet how granulocyte colony-stimulating factor (G-CSF) affects nonischemic cardiomyopathy, though its beneficial effects on acute myocardial infarction are well-established. We hypothesize that G-CSF beneficially might affect nonischemic cardiomyopathy through the direct cardioprotective effects. Here, we show that a single injection of doxorubicin (DOX, 15 mg/kg) induced left ventricular dilatation and dysfunction in mice within 2 weeks, and that these effects were significantly attenuated by human recombinant G-CSF (100 mg/kg/day for 5 days). G-CSF also protected hearts against DOX-induced cardiomyocyte atrophy/degeneration, fibrosis, inflammatory cell infiltration and down regulation of GATA-4 and sarcomeric proteins, myosin heavy chain, troponin I and desmin, both in vivo and in vitro. Cardiac cyclooxygenase-2 was upregulated and G-CSF receptor was downregulated in DOX-induced cardiomyopathy, but both of those effects were largely reversed by G-CSF. No DOX-induced apoptotic effects were seen, nor were there any changes in tumor necrosis factor-a or transforming growth factor-b1 levels. Among downstream mediators of G-CSF receptor signaling, DOX-induced cardiomyopathy involved inactivation of extracellular signal-regulated protein kinase (ERK); the ERK inactivation was reversed by G-CSF. Inhibition of ERK activation, but not cyclooxygenase-2 inhibition, completely abolished beneficial effect of G-CSF on cardiac function. G-CSF did not promote differentiation of bone marrow cells into cardiomyocytes according to the experiment using green fluorescent protein-chimeric mice, and inhibition of CXCR4 þ cell homing using AMD3100 did not diminish the effect of G-CSF. Finally, G-CSF was also effective when administered after cardiomyopathy was established. In conclusion, these findings imply the therapeutic usefulness of G-CSF mainly through restoring ERK activation against DOX-induced nonischemic cardiomyopathy.

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HIF‐1 Inhibitors for Cancer Therapy

Rapisarda

Melillo

2010

Tumor Microenvironment

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

Cited by 170 publications

References 38 publications

The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy

The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy

Granulocyte colony-stimulating factor improves left ventricular function of doxorubicin-induced cardiomyopathy

HIF‐1 Inhibitors for Cancer Therapy

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