Desferrioxamine Attenuates Doxorubicin-Induced Acute Cardiotoxicity through TFG-β/Smad p53 Pathway in Rat Model

Abstract

<jats:p>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-<jats:italic>β</jats:italic>, 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-<jats:italic>β</jats:italic>/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-<jats:italic>β</jats:italic>1/Smad pathway.</jats:p>

Melatonin combination with perindopril alleviated doxorubicin cardiac toxicity in L-NAME hypertensive rats: comparative study with perindopril

“…The cardiac oxidative stress promotes the development of cardiac fibrosis by upregulating TGF-β expression, which subsequently enhances cardiac collagen synthesis and suppresses collagen degradation in hypertensive rats. This is evidenced by increased cardiac percentage area of collagen fibers deposition in the present study (Zhao et al, 2008;Al-Shabanah et al, 2012), along with an increased level of cardiac TNF-α ( Pecoraro et al, 2016). All of these findings lead to significant cardiac pathology and increased mortality (Octavia et al, 2012).…”

Different Effects of Resveratrol on Dose-Related Doxorubicin-Induced Heart and Liver Toxicity

“…For that reason, participation of glycolysis pathway in ATP synthesis arises. Eventually, after months or years, the death of cardiomyocytes [24, 25] can consequently lead to heart failure [26, 27]. …”

Effects of cardiac biological activities on low-intensity physical training in doxorubicin-induced cardiotoxicity rat models

“…According to recent hypotheses, doxorubicin can directly cause cardiac toxicity and oxidative damage in a concentration-dependent manner and lead to the induction of myocardial toxicity and cardiac toxicity due to mitochondrial dysfunction through damage to mitochondrial DNA [19]. Inadequate mitochondrial function over time leads to synthesis acceleration within the adenosine triphosphate pathway, myocardial cell death after a few months, and eventually cardiomyopathy [10,[20][21][22]. According to our study, the LDH, CK, and glutathione concentration in serum were reliably different in each experimental groups and depended on a exercise.…”