Agustini Femmi Dwinda, Arozal Wawaimuli, Louisa Melva, Siswanto Soni, Soetikno Vivian, Nafrialdi Nafrialdi, Suyatna Franciscus
a Graduate Study in Biomedical Science and.
b Department of Pharmacology and Therapeutics , Faculty of Medicine, Universitas Indonesia , Central Jakarta , Indonesia.
Pharm Biol. 2016 Jul;54(7):1289-97. doi: 10.3109/13880209.2015.1073750. Epub 2015 Oct 6.
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.
This study determines whether the cardioprotective effect of MGR is caused by its effect on intracellular calcium regulation.
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-α), calcium regulatory gene (SERCA2a) and proapoptotic genes (caspase-9 and caspase-12), as well as cytosolic and mitochondrial calcium levels.
Treatment with MGR at 60 mg/kg bw/d significantly decreased the mRNA expression levels of TNF-α by 44.55% and caspase-9 by 52.79%, as well as the cytosolic calcium level by 24.15% (p < 0.05). SERCA2a and caspase-12 expressions were only slightly affected (27.27% increase and 24.85% decrease for SERCA2a and caspase-12, respectively, p > 0.05). Meanwhile, MGR 30 mg/kg bw/d gave insignificant results in all parameters.
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.
阿霉素（DOX）心脏毒性的分子机制涉及自由基的过度产生，这会导致细胞内钙调节异常和细胞凋亡。芒果苷（MGR）是一种天然存在的葡糖基黄酮，具有抗氧化和心脏保护特性。然而，其心脏保护机制尚未明确。
本研究旨在确定MGR的心脏保护作用是否由其对细胞内钙调节的影响所致。
雄性Sprague-Dawley大鼠腹腔注射DOX诱导，总剂量为15 mg/kg体重。MGR以30和60 mg/kg体重/天的剂量连续口服给药7周。检测的参数包括促炎细胞因子基因（TNF-α）、钙调节基因（SERCA2a）和促凋亡基因（caspase-9和caspase-12）的mRNA表达水平，以及细胞质和线粒体钙水平。
以60 mg/kg体重/天的剂量给予MGR治疗，可使TNF-α的mRNA表达水平显著降低44.55%，caspase-9降低52.79%，细胞质钙水平降低24.15%（p<0.05）。SERCA2a和caspase-12的表达仅受到轻微影响（SERCA2a和caspase-12分别增加27.27%和降低24.85%，p>0.05）。同时，30 mg/kg体重/天的MGR在所有参数上均未产生显著结果。
MGR通过下调促凋亡和促炎基因表达、上调SERCA2a基因表达以及使细胞质钙水平恢复正常，对DOX诱导的心脏炎症和细胞凋亡起到保护作用。因此，MGR的心脏保护作用至少部分归因于对细胞内钙稳态的调节。
