title: Zinc Prevents the Development of Diabetic Cardiomyopathy in db/db Mice.
abstract: Diabetic cardiomyopathy (DCM) is highly prevalent in type 2 diabetes (T2DM) patients. Zinc is an important essential trace metal, whose deficiency is associated with various chronic ailments, including vascular diseases. We assessed T2DM B6.BKS(D)-Leprdb/J (db/db) mice fed for six months on a normal diet containing three zinc levels (deficient, adequate, and supplemented), to explore the role of zinc in DCM development and progression. Cardiac function, reflected by ejection fraction, was significantly decreased, along with increased left ventricle mass and heart weight to tibial length ratio, in db/db mice. As a molecular cardiac hypertrophy marker, atrial natriuretic peptide levels were also significantly increased. Cardiac dysfunction and hypertrophy were accompanied by significantly increased fibrotic (elevated collagen accumulation as well as transforming growth factor β and connective tissue growth factor levels) and inflammatory (enhanced expression of tumor necrosis factor alpha, interleukin-1β, caspase recruitment domain family member 9, and B-cell lymphoma/leukemia 10, and activated p38 mitogen-activated protein kinase) responses in the heart. All these diabetic effects were exacerbated by zinc deficiency, and not affected by zinc supplementation, respectively. Mechanistically, oxidative stress and damage, mirrored by the accumulation of 3-nitrotyrosine and 4-hydroxy-2-nonenal, was significantly increased along with significantly decreased expression of Nrf2 and its downstream antioxidants (NQO-1 and catalase). This was also exacerbated by zinc deficiency in the db/db mouse heart. These results suggested that zinc deficiency promotes the development and progression of DCM in T2DM db/db mice. The exacerbated effects by zinc deficiency on the heart of db/db mice may be related to further suppression of Nrf2 expression and function.
authors.affiliation: Cardiovascular Center & Geriatric Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin, China. wangshudong816@163.com.|Pediatric Research Institute, The Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA. wangshudong816@163.com.
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
authors.affiliation: Pediatric Research Institute, The Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA. wangbw@jlu.edu.cn.|Gynecology and Obstetrics, The Second Hospital of Jilin University, Changchun 130041, Jilin, China. wangbw@jlu.edu.cn.
authors.forename: Bowei
authors.initials: B
authors.lastname: Wang
authors.affiliation: Cardiovascular Center & Geriatric Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin, China. yuehuiwang300@hotmail.com.
authors.forename: Yuehui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Cardiovascular Center & Geriatric Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin, China. tongqian@126.com.
authors.forename: Qian
authors.initials: Q
authors.lastname: Tong
authors.affiliation: Cardiovascular Center & Geriatric Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin, China. liuquan@jlu.edu.cn.
authors.forename: Quan
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Cardiovascular Center & Geriatric Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin, China. sunjian@163.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.affiliation: Cardiovascular Center & Geriatric Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin, China. zhengyang@jlu.edu.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Pediatric Research Institute, The Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA. l0cai001@louisville.edu.|Wendy Novak Diabetes Care Center, Departments of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA. l0cai001@louisville.edu.
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D058065:Diabetic Cardiomyopathies / Q000209:etiology* / Q000378:metabolism* / Q000517:prevention & control; D019587:Dietary Supplements; D004195:Disease Models, Animal; D005355:Fibrosis; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000008:administration & dosage*; D015032:Zinc / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D020011:Protective Agents; D015032:Zinc
keywords: diabetic cardiomyopathy; inflammation; nuclear factor-erythroid 2-related factor 2; oxidative stress; zinc supplement