title: Both selenium deficiency and modest selenium supplementation lead to myocardial fibrosis in mice via effects on redox-methylation balance.
abstract: METHODS
  Selenium has complex effects in vivo on multiple homeostatic mechanisms such as redox balance, methylation balance, and epigenesis, via its interaction with the methionine-homocysteine cycle. In this study, we examined the hypothesis that selenium status would modulate both redox and methylation balance and thereby modulate myocardial structure and function.
  
  
  RESULTS
  We examined the effects of selenium-deficient (<0.025 mg/kg), control (0.15 mg/kg), and selenium-supplemented (0.5 mg/kg) diets on myocardial histology, biochemistry and function in adult C57/BL6 mice. Selenium deficiency led to reactive myocardial fibrosis and systolic dysfunction accompanied by increased myocardial oxidant stress. Selenium supplementation significantly reduced methylation potential, DNA methyltransferase activity and DNA methylation. In mice fed the supplemented diet, inspite of lower oxidant stress, myocardial matrix gene expression was significantly altered resulting in reactive myocardial fibrosis and diastolic dysfunction in the absence of myocardial hypertrophy.
  
  
  CONCLUSIONS
  Our results indicate that both selenium deficiency and modest selenium supplementation leads to a similar phenotype of abnormal myocardial matrix remodeling and dysfunction in the normal heart. The crucial role selenium plays in maintaining the balance between redox and methylation pathways needs to be taken into account while optimizing selenium status for prevention and treatment of heart failure.
authors.affiliation: VA Boston Healthcare System, West Roxbury, MA 02132, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Metes-Kosik
authors.forename: Ivan
authors.initials: I
authors.lastname: Luptak
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Dibello
authors.forename: Diane E
authors.initials: DE
authors.lastname: Handy
authors.forename: Shiow-Shih
authors.initials: SS
authors.lastname: Tang
authors.forename: Hui
authors.initials: H
authors.lastname: Zhi
authors.forename: Fuzhong
authors.initials: F
authors.lastname: Qin
authors.forename: Donald W
authors.initials: DW
authors.lastname: Jacobsen
authors.forename: Joseph
authors.initials: J
authors.lastname: Loscalzo
authors.forename: Jacob
authors.initials: J
authors.lastname: Joseph
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000503:physiopathology; D003545:Cysteine / Q000097:blood; D019175:DNA Methylation / Q000187:drug effects*; D004032:Diet; D019587:Dietary Supplements; D057890:Epigenomics; D005355:Fibrosis; D005978:Glutathione / Q000097:blood; D006710:Homocysteine / Q000097:blood; D028421:Isoprostanes / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects*; D060888:Real-Time Polymerase Chain Reaction; D012643:Selenium / Q000097:blood / Q000172:deficiency* / Q000494:pharmacology*; D051140:Selenoproteins / Q000235:genetics / Q000378:metabolism
chemical_list: D028421:Isoprostanes; D051140:Selenoproteins; D006710:Homocysteine; D005978:Glutathione; D012643:Selenium; D003545:Cysteine