title: Cardioprotection mechanism of mangiferin on doxorubicin-induced rats: Focus on intracellular calcium regulation.
abstract: BACKGROUND
  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.
  
  
  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-α), 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-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a Graduate Study in Biomedical Science and.
authors.forename: Femmi Dwinda
authors.initials: FD
authors.lastname: Agustini
authors.affiliation: b Department of Pharmacology and Therapeutics , Faculty of Medicine, Universitas Indonesia , Central Jakarta , Indonesia.
authors.forename: Wawaimuli
authors.initials: W
authors.lastname: Arozal
authors.affiliation: b Department of Pharmacology and Therapeutics , Faculty of Medicine, Universitas Indonesia , Central Jakarta , Indonesia.
authors.forename: Melva
authors.initials: M
authors.lastname: Louisa
authors.affiliation: a Graduate Study in Biomedical Science and.
authors.forename: Soni
authors.initials: S
authors.lastname: Siswanto
authors.affiliation: b Department of Pharmacology and Therapeutics , Faculty of Medicine, Universitas Indonesia , Central Jakarta , Indonesia.
authors.forename: Vivian
authors.initials: V
authors.lastname: Soetikno
authors.affiliation: b Department of Pharmacology and Therapeutics , Faculty of Medicine, Universitas Indonesia , Central Jakarta , Indonesia.
authors.forename: Nafrialdi
authors.initials: N
authors.lastname: Nafrialdi
authors.affiliation: b Department of Pharmacology and Therapeutics , Faculty of Medicine, Universitas Indonesia , Central Jakarta , Indonesia.
authors.forename: Franciscus
authors.initials: F
authors.lastname: Suyatna
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D066126:Cardiotoxicity; D053454:Caspase 12 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin; D005786:Gene Expression Regulation; D006331:Heart Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; C506948:Atp2a2 protein, rat; D018836:Inflammation Mediators; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D044004:Xanthones; C013592:mangiferin; D004317:Doxorubicin; C506443:Casp12 protein, rat; C506435:Casp9 protein, rat; D053454:Caspase 12; D053453:Caspase 9; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
keywords: Apoptosis; SERCA2a; cardiotoxicity; inflammation