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Desferrioxamine attenuates doxorubicin-induced acute cardiotoxicity through TFG-β/Smad p53 pathway in rat model.

Al-Shabanah OA, Aleisa AM, Hafez MM, Al-Rejaie SS, Al-Yahya AA, Bakheet SA, Al-Harbi MM, Sayed-Ahmed MM - Oxid Med Cell Longev (2012)

Bottom Line: Interaction of doxorubicin DOX with iron and the consequent generation of reactive oxygen species (ROS) is a major player in DOX-induced cardiomyopathy.A single dose of DOX significantly increased mRNA expression of TGF-β, Smad2, Smad4, CDKN2A and p53 and significantly decreased Samd7 and Mdm2 mRNA expression levels.Administration of DFX prior to DOX resulted in a complete reversal of DOX-induced alteration in cardiac enzymes and gene expression to normal levels.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia. shabanah@ksu.edu.sa

ABSTRACT
Interaction of doxorubicin DOX with iron and the consequent generation of reactive oxygen species (ROS) is a major player in DOX-induced cardiomyopathy. Accordingly, this study has been initiated to investigate the preventive effect of the iron chelator, desferrioxamine (DFX), against DOX-induced acute cardiotoxicity in rats. Male Wistar albino rats were divided into four groups and were injected intraperitoneally (I.P.) with normal saline, a single dose of DOX (15 mg/kg), a single dose of DFX (250 mg/kg) and a combined treatment with DFX (250 mg/kg) 30 min prior to a single dose of DOX, (15 mg/kg). A single dose of DOX significantly increased mRNA expression of TGF-β, Smad2, Smad4, CDKN2A and p53 and significantly decreased Samd7 and Mdm2 mRNA expression levels. Administration of DFX prior to DOX resulted in a complete reversal of DOX-induced alteration in cardiac enzymes and gene expression to normal levels. Data from this study suggest that (1) DOX induces its acute cardiotoxicity secondary to increasing genes expression of TGF-β/Smad pathway. (2) DOX increases apoptosis through upregulation of CDKN2A and p53 and downregulation of Mdm2 gene expression. (3) The preventive effect of DFX against DOX-induced cardiotoxicity is mediated via the TGF-β1/Smad pathway.

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Related in: MedlinePlus

Effect of DOX, DFX, and their combination on the expression levels of Smad2 (a) and Smad4 (b) in rat heart tissues. Data are presented as mean ± SD (n = 10). *, # and $ indicate significant change from control, DFX and DOX plus DFX, respectively, at P < 0.05.
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fig2: Effect of DOX, DFX, and their combination on the expression levels of Smad2 (a) and Smad4 (b) in rat heart tissues. Data are presented as mean ± SD (n = 10). *, # and $ indicate significant change from control, DFX and DOX plus DFX, respectively, at P < 0.05.

Mentions: Figure 2 shows the effect of DOX, DFX, and their combination on the gene expression level of Smad2 (a) and Smad4 (b) in rat heart tissue. Treatment with a single dose of DOX was resulted in significant increases in the gene expression of Smad2 and Smad4 by 3.8- and 4-folds, respectively, compared to the control group. Interestingly, DFX pretreatment in combination with DOX resulted in a complete reversal change of Smad2 and 4 induced by DOX to the normal expression levels.


Desferrioxamine attenuates doxorubicin-induced acute cardiotoxicity through TFG-β/Smad p53 pathway in rat model.

Al-Shabanah OA, Aleisa AM, Hafez MM, Al-Rejaie SS, Al-Yahya AA, Bakheet SA, Al-Harbi MM, Sayed-Ahmed MM - Oxid Med Cell Longev (2012)

Effect of DOX, DFX, and their combination on the expression levels of Smad2 (a) and Smad4 (b) in rat heart tissues. Data are presented as mean ± SD (n = 10). *, # and $ indicate significant change from control, DFX and DOX plus DFX, respectively, at P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3350848&req=5

fig2: Effect of DOX, DFX, and their combination on the expression levels of Smad2 (a) and Smad4 (b) in rat heart tissues. Data are presented as mean ± SD (n = 10). *, # and $ indicate significant change from control, DFX and DOX plus DFX, respectively, at P < 0.05.
Mentions: Figure 2 shows the effect of DOX, DFX, and their combination on the gene expression level of Smad2 (a) and Smad4 (b) in rat heart tissue. Treatment with a single dose of DOX was resulted in significant increases in the gene expression of Smad2 and Smad4 by 3.8- and 4-folds, respectively, compared to the control group. Interestingly, DFX pretreatment in combination with DOX resulted in a complete reversal change of Smad2 and 4 induced by DOX to the normal expression levels.

Bottom Line: Interaction of doxorubicin DOX with iron and the consequent generation of reactive oxygen species (ROS) is a major player in DOX-induced cardiomyopathy.A single dose of DOX significantly increased mRNA expression of TGF-β, Smad2, Smad4, CDKN2A and p53 and significantly decreased Samd7 and Mdm2 mRNA expression levels.Administration of DFX prior to DOX resulted in a complete reversal of DOX-induced alteration in cardiac enzymes and gene expression to normal levels.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia. shabanah@ksu.edu.sa

ABSTRACT
Interaction of doxorubicin DOX with iron and the consequent generation of reactive oxygen species (ROS) is a major player in DOX-induced cardiomyopathy. Accordingly, this study has been initiated to investigate the preventive effect of the iron chelator, desferrioxamine (DFX), against DOX-induced acute cardiotoxicity in rats. Male Wistar albino rats were divided into four groups and were injected intraperitoneally (I.P.) with normal saline, a single dose of DOX (15 mg/kg), a single dose of DFX (250 mg/kg) and a combined treatment with DFX (250 mg/kg) 30 min prior to a single dose of DOX, (15 mg/kg). A single dose of DOX significantly increased mRNA expression of TGF-β, Smad2, Smad4, CDKN2A and p53 and significantly decreased Samd7 and Mdm2 mRNA expression levels. Administration of DFX prior to DOX resulted in a complete reversal of DOX-induced alteration in cardiac enzymes and gene expression to normal levels. Data from this study suggest that (1) DOX induces its acute cardiotoxicity secondary to increasing genes expression of TGF-β/Smad pathway. (2) DOX increases apoptosis through upregulation of CDKN2A and p53 and downregulation of Mdm2 gene expression. (3) The preventive effect of DFX against DOX-induced cardiotoxicity is mediated via the TGF-β1/Smad pathway.

Show MeSH
Related in: MedlinePlus