title: Metallothionein Is Downstream of Nrf2 and Partially Mediates Sulforaphane Prevention of Diabetic Cardiomyopathy.
abstract: We have reported that sulforaphane (SFN) prevented diabetic cardiomyopathy in both type 1 and type 2 diabetes (T2DM) animal models via the upregulation of nuclear transcription factor erythroid 2-related factor 2 (Nrf2) and metallothionein (MT). In this study, we tested whether SFN protects the heart from T2DM directly through Nrf2, MT, or both. Using Nrf2-knockout (KO), MT-KO, and wild-type (WT) mice, T2DM was induced by feeding a high-fat diet for 3 months followed by a small dose of streptozotocin. Age-matched controls were given a normal diet. Both T2DM and control mice were then treated with or without SFN for 4 months by continually feeding a high-fat or normal diet. SFN prevented diabetes-induced cardiac dysfunction as well as diabetes-associated cardiac oxidative damage, inflammation, fibrosis, and hypertrophy, with increases in Nrf2 and MT expressions in the WT mice. Both Nrf2-KO and MT-KO diabetic mice exhibited greater cardiac damage than WT diabetic mice. SFN did not provide cardiac protection in Nrf2-KO mice, but partially or completely protected the heart from diabetes in MT-KO mice. SFN did not induce MT expression in Nrf2-KO mice, but stimulated Nrf2 function in MT-KO mice. These results suggest that Nrf2 plays the indispensable role for SFN cardiac protection from T2DM with significant induction of MT and other antioxidants. MT expression induced by SFN is Nrf2 dependent, but is not indispensable for SFN-induced cardiac protection from T2DM.
authors.affiliation: The First Hospital of Jilin University, Changchun, Jilin, China.|Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, Zhejiang, China.|Department of Pediatrics, Pediatric Research Institute, University of Louisville, Louisville, KY.
authors.forename: Junlian
authors.initials: J
authors.lastname: Gu
authors.affiliation: The First Hospital of Jilin University, Changchun, Jilin, China.|Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, Zhejiang, China.|Department of Pediatrics, Pediatric Research Institute, University of Louisville, Louisville, KY.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Pediatrics, Pediatric Research Institute, University of Louisville, Louisville, KY.|The Second Hospital of Jilin University, Changchun, Jilin, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: The First Hospital of Jilin University, Changchun, Jilin, China.|Department of Pediatrics, Pediatric Research Institute, University of Louisville, Louisville, KY.
authors.forename: Lili
authors.initials: L
authors.lastname: Kong
authors.affiliation: The First Hospital of Jilin University, Changchun, Jilin, China.|Department of Pediatrics, Pediatric Research Institute, University of Louisville, Louisville, KY.
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
authors.affiliation: The First Hospital of Jilin University, Changchun, Jilin, China.|Department of Pediatrics, Pediatric Research Institute, University of Louisville, Louisville, KY.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xu
authors.affiliation: The First Hospital of Jilin University, Changchun, Jilin, China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, Zhejiang, China.|Department of Pediatrics, Pediatric Research Institute, University of Louisville, Louisville, KY.|Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Pediatrics, Pediatric Research Institute, University of Louisville, Louisville, KY.|Kosair Charities Pediatric Heart Research Program, Cardiovascular Innovation Institute, University of Louisville, Louisville, KY.
authors.forename: Bradley B
authors.initials: BB
authors.lastname: Keller
authors.affiliation: The First Hospital of Jilin University, Changchun, Jilin, China.
authors.forename: Honglan
authors.initials: H
authors.lastname: Zhou
authors.affiliation: The First Hospital of Jilin University, Changchun, Jilin, China yuehuiwang300@hotmail.com renalxu@163.com.
authors.forename: Yuehui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The First Hospital of Jilin University, Changchun, Jilin, China yuehuiwang300@hotmail.com renalxu@163.com.
authors.forename: Zhonggao
authors.initials: Z
authors.lastname: Xu
authors.affiliation: The First Hospital of Jilin University, Changchun, Jilin, China.|Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, Zhejiang, China.|Department of Pediatrics, Pediatric Research Institute, University of Louisville, Louisville, KY.|Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY.
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D058065:Diabetic Cardiomyopathies / Q000000981:diagnostic imaging / Q000209:etiology / Q000378:metabolism*; D059305:Diet, High-Fat; D004452:Echocardiography; D006321:Heart / Q000187:drug effects*; D017879:Isothiocyanates / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008668:Metallothionein / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013454:Sulfoxides; D015854:Up-Regulation
chemical_list: D016588:Anticarcinogenic Agents; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D013454:Sulfoxides; D008668:Metallothionein; C016766:sulforaphane