Cardioprotection mechanism of mangiferin on doxorubicin-induced rats: Focus on intracellular calcium regulation

Abstract

Context: The molecular mechanism of doxorubicin (DOX) cardiotoxicity involves overproduction of free radicals that leads to intracellular calcium dysregulation and apoptosis. Mangiferin (MGR), a naturally occurring glucosylxanthone, has antioxidant and cardioprotective properties. However, its cardioprotection mechanism has yet to be revealed. Objective: This study determines whether the cardioprotective effect of MGR is caused by its effect on intracellular calcium regulation. Materials and methods: Male Sprague-Dawley rats were induced by DOX intraperitoneally with a total dose of 15 mg/kg bw. MGR was given orally at the doses of 30 and 60 mg/kg bw/d for seven consecutive weeks. The parameters examined were mRNA expression levels of proinflammatory cytokine gene (TNF-a), calcium regulatory gene (SERCA2a) and proapoptotic genes (caspase-9 and caspase-12), as well as cytosolic and mitochondrial calcium levels. Results: Treatment with MGR at 60 mg/kg bw/d significantly decreased the mRNA expression levels of TNF-a by 44.55% and caspase-9 by 52.79%, as well as the cytosolic calcium level by 24.15% (p50.05). SERCA2a and caspase-12 expressions were only slightly affected (27.27% increase and 24.85% decrease for SERCA2a and caspase-12, respectively, p40.05). Meanwhile, MGR 30 mg/kg bw/d gave insignificant results in all parameters. Discussion and conclusion: MGR protected against DOX-induced cardiac inflammation and apoptosis via down-regulation of proapoptotic and proinflammatory gene expressions, upregulation of SERCA2a gene expression, and normalization of cytosolic calcium level. Thus, the cardioprotective effect of MGR is at least in part due to the regulation of intracellular calcium homeostasis. ARTICLE HISTORY

Protective effect of mangiferin on myocardial ischemia-reperfusion injury in streptozotocin-induced diabetic rats: role of AGE-RAGE/MAPK pathways

“…Similarly, in this present study, there was increased expression of JNK, p38, Bax and decreased expression of ERK1/2 and Bcl-2 in the diabetes + IR group while an opposite effect was seen in the mangiferin treatment group. The present results are in accordance with the previous findings which demonstrate that anti-apoptotic property of mangiferin is responsible for its cardioprotective effect 23 49 .…”

Insights into Doxorubicin-induced Cardiotoxicity: Molecular Mechanisms, Preventive Strategies, and Early Monitoring

“…Findings from this study concluded that mtDNA depletion and its associated ETC impairment preceded calcium level disruption (Lebrecht et al, 2010). Nevertheless, targeting calcium dysfunction still remains a viable approach to treat DOX-mediated cardiotoxicity (Agustini et al, 2016;Gao et al, 2016).…”

Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity

“…It is noteworthy that vitamin C, a well-known reductant, can evidently decline the levels of TNFα, IL-1β and IL-6 in DOX-treated mice, indicating that oxidation/nitrosation stress may be one of the targets of cardiac protection during DOX treatment (Akolkar et al, 2017). In addition, the intracellular calcium homeostasis protective agent mangiferin was also verified to be able to relieve the up-regulation of TNFα and caspase-9 induced by DOX and stimulates the calcium regulatory gene, preventing myocarditis and apoptosis (Agustini et al, 2016).…”