α-Linolenic acid attenuates doxorubicin-induced cardiotoxicity in rats through suppression of oxidative stress and apoptosis

Abstract

Doxorubicin (DOX), a widely used anti-tumor drug, can give rise to severe cardiotoxicity by oxidative stress and cell apoptosis, which restricts its clinical application. α-Linolenic acid (ALA) has been shown to serve as a potent cardioprotective agent. The aim of this study was to explore the protective effects of ALA on DOX-induced cardiotoxicity and the underlying molecular mechanisms for this cardioprotection in rats. Rats were randomly divided into four groups and administrated with normal saline, ALA (500 µg/kg), DOX (2.5 mg/kg), or ALA (500 µg/kg) plus DOX (2.5 mg/kg) for 17 days. The results showed that DOX treatment significantly increased the heart weight/body weight, liver wet weight (WW)/dry weight (DW), lung WW/DW, serum levels of brain natriuretic peptide, creatine kinase-MB, lactate dehydrogenase, and cardiac troponin I, myocardial necrosis and myocardial malondialdehyde content, and induced the mRNA expression of Nrf2 in the nucleus, cleaved caspase-3, Bax, and superoxide dismutase (SOD). In addition, DOX led to a significant decrease in left ventricular end-diastolic volume, stroke volume, ejection fraction, SOD, glutathione-peroxidase, catalase, as well as the expression of Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm, phospho-AKT, phospho-ERK, and Bcl-2. Co-treatment with ALA significantly eliminated these changes induced by DOX except further reduction of Keap1 and elevation of Nrf2 and SOD mRNA. These results showed the cardioprotective effects of ALA on DOX-induced cardiotoxicity in rats. The mechanisms might be associated with the enhancement of antioxidant defense system through activating Keap1/Nrf2 pathway and anti-apoptosis through activating protein kinase B/extracellular signal regulated kinase pathway. Our results suggested a promising future of ALA-based preventions and therapies for myocardial damage after administration of DOX.

Effect of valsartan on cardiac senescence and apoptosis in a rat model of cardiotoxicity

“…The results of the present study showed a significant increase of cardiac TBARS content with decrease of anti-oxidants in DOX-treated rats (Figures 1 and 2), suggesting the primary role of oxidative stress in DOX cardiotoxicity. These data are in agreement with earlier studies (Yu et al 2013). Moreover, the reactive oxygen species (ROS) leads to depletion of the endogenous antioxidant system and oxidative injury.…”

“…In the current work, our results revealed that DOX could induce cardiomyocyte apoptosis, as evaluated by decreased Bcl-2 and increased Bax gene expression (Figures 4 and 5), suggesting that apoptosis is one of the major contributors of DOX-imposed cardiac toxicity. These results were in agreement with previous studies (Yu et al 2013). Accumulated data suggest that cardiomyocyte apoptosis and death in response to DOX are mainly mediated by increased oxidative stress (Smith et al 2010).…”

“…The present study demonstrated that the activities of CK-MB and LDH in serum are significantly increased in DOX group compared with control group (Table 3). These results were in line with those of Iqbal et al (2008) and Yu et al (2013). In contrast, the reduction of DOX-induced increase in the activities of serum LDH and CK-MB by concurrent or post but not pre treatment of animals with valsartan indicates suppression of cardiac injury; thereby supporting that valsartan has cardioprotective…”

“…Moreover, the reactive oxygen species (ROS) leads to depletion of the endogenous antioxidant system and oxidative injury. Superoxide dismutase, glutathione peroxidase and catalase constitute the first line of cellular defense against ROS, because they can decompose superoxide anions and hydrogen peroxide before their interaction to form the more reactive hydroxyl radical (Yu et al 2013). In accordance with these studies, the results of the current work demonstrated a significant decrease in the cardiac total anti-oxidants in DOX-treated animals ( Figures 1 and 2).…”

Ginsenoside Rg3 antagonizes adriamycin-induced cardiotoxicity by improving endothelial dysfunction from oxidative stress via upregulating the Nrf2-ARE pathway through the activation of akt

“…Moderation of inflammatory factors helps Rg3 to antagonize ADM-Induced cardiotoxicity from oxidative stress. previous reports revealed that ADM-induced cardiotoxicity is associated with multiple signaling pathways (Kotamraju et al 2000;Negoro et al 2001;Yu et al 2013). The transcription factor Nrf2 plays a central role in the inducible expression of many cytoprotective genes in response to oxidative stresses (Taguchi et al 2011).…”