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  • Title: All-trans-retinoic acid ameliorates doxorubicin-induced cardiotoxicity: in vivo potential involvement of oxidative stress, inflammation, and apoptosis via caspase-3 and p53 down-expression.
    Author: Khafaga AF, El-Sayed YS.
    Journal: Naunyn Schmiedebergs Arch Pharmacol; 2018 Jan; 391(1):59-70. PubMed ID: 29085977.
    Abstract:
    The present study aimed to investigate the potential protective effect of all-trans-retinoic acid (ATRA, a natural derivative of vitamin A) against doxorubicin (DOX)-induced in vivo cardiac toxicity and its underlying mechanisms. Forty male albino rats were allocated into control, ATRA (0.5 mg/kg bwt, intraperitoneally daily), DOX (2.5 mg/kg bwt, intraperitoneally twice weekly for 3 weeks), and DOX + ATRA groups. Serum lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase-cardiac type (CK-MB), troponin I, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) were measured. In addition, cardiac glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT), and malondialdehyde (MDA) were determined. Cardiac tissues were examined for histopathologic changes and immunoexpression of pro-apoptotic caspase 3 and tumor-suppressor p53 proteins. DOX caused severe myocardial damage; degenerative and necrotic changes and worsened cardiac function biomarkers; and elevated serum LDH, CK, CK-MB, and troponin I. In addition, DOX inhibited cardiac antioxidative enzymes (GSH, GSH-Px, SOD, CAT) activities and enhanced MDA level. DOX increased serum proinflammatory cytokines (TNF-α, IL-6) and area percent of caspase 3 and p53 immunoexpression in heart tissues. Pretreatment with ATRA maintained cardiac function biomarkers, and reduced proinflammatory cytokines, lipid peroxidation, and immunoexpression of caspase 3 and p53. Moreover, ATRA improved cardiac histoarchitecture, as well as the activities of antioxidative enzymes. Collectively, ATRA can counteract DOX-induced cardiomyopathy through antioxidative and anti-inflammatory properties, besides suppression of the activation of the mitochondrial apoptotic pathway.
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