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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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Effect of DOX, DFX, and their combination on the expression levels of TGF-β (a) and Smad7 (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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fig1: Effect of DOX, DFX, and their combination on the expression levels of TGF-β (a) and Smad7 (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: The expression levels of TGF-β1, Smad2, Samd4, Smad7, CDKN2A, Mdm2, and p53 genes are studied in heart tissue, to investigate whether DOX treatment stimulates the TGF-β1 signaling cascade that leads to cardiac apoptosis. The effect of DOX and its combination with DFX on TGF-β1 expression was shown in Figure 1. A single dose of DOX resulted in significant increase in the gene expression of TGF-β1 by 5.6-folds and decrease in Smad7 by 0.5-fold expressions, compared to the control group. On the other hand, pretreatment with DFX, 30 minuets before DOX treatment, induced a significant repair of the DOX-induced alteration in the gene expression of TGF-β1 and Smad7 compared 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 TGF-β (a) and Smad7 (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

fig1: Effect of DOX, DFX, and their combination on the expression levels of TGF-β (a) and Smad7 (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: The expression levels of TGF-β1, Smad2, Samd4, Smad7, CDKN2A, Mdm2, and p53 genes are studied in heart tissue, to investigate whether DOX treatment stimulates the TGF-β1 signaling cascade that leads to cardiac apoptosis. The effect of DOX and its combination with DFX on TGF-β1 expression was shown in Figure 1. A single dose of DOX resulted in significant increase in the gene expression of TGF-β1 by 5.6-folds and decrease in Smad7 by 0.5-fold expressions, compared to the control group. On the other hand, pretreatment with DFX, 30 minuets before DOX treatment, induced a significant repair of the DOX-induced alteration in the gene expression of TGF-β1 and Smad7 compared 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