title: Zinc rescue of Akt2 gene deletion-linked murine cardiac dysfunction and pathological changes is metallothionein-dependent.
abstract: We have demonstrated that zinc supplementation provides cardiac protection from diabetes in mice, but its underlying mechanism remains unclear. Since zinc mimics the function of insulin, it may provide benefit to the heart via stimulating Akt-mediated glucose metabolism. Akt2 plays an important role in cardiac glucose metabolism and mice with Akt2 gene deletion (Akt2-KO) exhibit a type 2 diabetes phenotype; therefore, we assumed that no cardiac protection by zinc supplementation from diabetes would be observed in Akt2-KO mice. Surprisingly, despite Akt2 gene deletion, zinc supplementation provided protection against cardiac dysfunction and other pathological changes in Akt2-KO mice, which were accompanied by significant decreases in Akt and GSK-3β phosphorylation. Correspondingly, glycogen synthase phosphorylation and hexokinase II and PGC-1α expression, all involved in the regulation of glucose metabolism, were significantly altered in diabetic hearts, along with a significantly increased expression of Akt negative regulators: PTEN, PTP1B, and TRB3. All these molecular, pathological, and functional changes were significantly prevented by 3-month zinc supplementation. Furthermore, the stimulation of Akt-mediated glucose metabolic kinases or enzymes by zinc treatment was metallothionein-dependent since it could not be observed in metallothionein-knockout mice. These results suggest that zinc preserves cardiac function and structure in Akt2-KO mice presumably due to its insulin mimetic effect on cardiac glucose-metabolism. The cardioprotective effects of zinc are metallothionein-dependent. This is very important since zinc supplementation may be required for patients with Akt2 gene deficiency or insulin resistance.
authors.affiliation: The First Hospital of Jilin University, Jilin 130021, China; Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, KY 40202, USA.
authors.forename: Weixia
authors.initials: W
authors.lastname: Sun
authors.affiliation: Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, KY 40202, USA; The Second Hospital of Jilin University, Jilin 130041, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Miao
authors.affiliation: The First Hospital of Jilin University, Jilin 130021, China; Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, KY 40202, USA.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhou
authors.affiliation: The First Hospital of Jilin University, Jilin 130021, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville, KY 40202, USA.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Epstein
authors.affiliation: Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, KY 40202, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mellen
authors.affiliation: The First Hospital of Jilin University, Jilin 130021, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: The First Hospital of Jilin University, Jilin 130021, China.
authors.forename: Yaowen
authors.initials: Y
authors.lastname: Fu
authors.affiliation: The First Hospital of Jilin University, Jilin 130021, China. Electronic address: yuehuiwang300@hotmail.com.
authors.forename: Yuehui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville, KY 40202, USA. Electronic address: l0cai001@louisville.edu.
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006006:Glycogen Synthase / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015032:Zinc / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D018797:Cell Cycle Proteins; D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C474830:TRB3 protein, mouse; D014157:Transcription Factors; D008668:Metallothionein; D006006:Glycogen Synthase; D006593:Hexokinase; C494922:Akt2 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D015032:Zinc
keywords: Akt2 knockout; Diabetic heart; GSK-3β; Insulin resistance; Metallothionein; Zinc