title: Cardiac metallothionein induction plays the major role in the prevention of diabetic cardiomyopathy by zinc supplementation.
abstract: BACKGROUND
  Our previous studies showed that transgenic mice that overexpress cardiac-specific metallothionein (MT) are highly resistant to diabetes-induced cardiomyopathy. Zinc is the major metal that binds to MT under physiological conditions and is a potent inducer of MT. The present study therefore explored whether zinc supplementation can protect against diabetic cardiomyopathy through cardiac MT induction.
  
  
  RESULTS
  Diabetes was induced in mice (C57BL/6J strain) by a single injection of streptozotocin. Half were supplemented intraperitoneally with zinc sulfate (5 mg/kg) every other day for 3 months. After zinc supplementation, mice were maintained for 3 more months and then examined for cardiomyopathy by functional and morphological analysis. Significant increases in cardiac morphological impairment, fibrosis, and dysfunction were observed in diabetic mice but not in diabetic mice supplemented with zinc. Zinc supplementation also induced a significant increase in cardiac MT expression. The role of MT in cardiac protection by zinc supplementation was examined in cultured cardiac cells that were directly exposed to high levels of glucose (HG) and free fatty acid (FFA) (palmitate), treatment that mimics diabetic conditions. Cell survival rate was significantly decreased for cells exposed to HG/FFA but did not change for cells exposed to HG/FFA and pretreated with zinc or low-dose cadmium, each of which induces significant MT synthesis. When MT expression was silenced with the use of MT small-interfering RNA, the preventive effect of pretreatment with zinc or low-dose cadmium was abolished.
  
  
  CONCLUSIONS
  These results suggest that the prevention of diabetic cardiomyopathy by zinc supplementation is predominantly mediated by an increase in cardiac MT.
authors.affiliation: Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Jianxun
authors.initials: J
authors.lastname: Wang
authors.forename: Ye
authors.initials: Y
authors.lastname: Song
authors.forename: Laila
authors.initials: L
authors.lastname: Elsherif
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Song
authors.forename: Guihua
authors.initials: G
authors.lastname: Zhou
authors.forename: Sumanth D
authors.initials: SD
authors.lastname: Prabhu
authors.forename: Jack T
authors.initials: JT
authors.lastname: Saari
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
mesh_terms: D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D048909:Diabetes Complications / Q000378:metabolism / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D005230:Fatty Acids, Nonesterified / Q000633:toxicity; D005947:Glucose / Q000633:toxicity; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering; D019287:Zinc Sulfate / Q000494:pharmacology*
chemical_list: D005230:Fatty Acids, Nonesterified; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D002104:Cadmium; D019287:Zinc Sulfate; D008668:Metallothionein; D005947:Glucose