Zinc deficiency and cellular oxidative stress: prognostic implications in cardiovascular diseases

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Abstract

Zinc is an essential nutrient for human health and has anti-oxidative stress and anti-inflammatory functions. The association between zinc deficiency and the development of cardiovascular diseases (CVDs) has been supported by numerous studies. Supplementing zinc can reduce the risk of atherosclerosis and protect against myocardial infarction and ischemia/reperfusion injury. In this review we summarize the evidence in the literature, to consolidate the current knowledge on the dysregulation of zinc homeostasis in CVDs, and to explore the significant roles of the zinc homeostasis-regulatory proteins in cardiac physiology and pathophysiology. Moreover, this review also deliberates on the potential diagnostic and prognostic implications of zinc/zinc homeostasis-associated molecules (ZIP, ZnT, and MTs) in CVDs.

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A genome-wide association study identifies novel risk loci for type 2 diabetes.

Robert Sladek, Ghislain Rocheleau, Johan Rung … (2007)

Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case-control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort. This identified four loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene. These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively in insulin-producing beta-cells, and two linkage disequilibrium blocks that contain genes potentially involved in beta-cell development or function (IDE-KIF11-HHEX and EXT2-ALX4). These associations explain a substantial portion of disease risk and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.

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The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes.

Janet Wenzlau, Kirstine Juhl, Liping Yu … (2007)

Type 1 diabetes (T1D) results from progressive loss of pancreatic islet mass through autoimmunity targeted at a diverse, yet limited, series of molecules that are expressed in the pancreatic beta cell. Identification of these molecular targets provides insight into the pathogenic process, diagnostic assays, and potential therapeutic agents. Autoantigen candidates were identified from microarray expression profiling of human and rodent pancreas and islet cells and screened with radioimmunoprecipitation assays using new-onset T1D and prediabetic sera. A high-ranking candidate, the zinc transporter ZnT8 (Slc30A8), was targeted by autoantibodies in 60-80% of new-onset T1D compared with <2% of controls and <3% type 2 diabetic and in up to 30% of patients with other autoimmune disorders with a T1D association. ZnT8 antibodies (ZnTA) were found in 26% of T1D subjects classified as autoantibody-negative on the basis of existing markers [glutamate decarboxylase (GADA), protein tyrosine phosphatase IA2 (IA2A), antibodies to insulin (IAA), and islet cytoplasmic autoantibodies (ICA)]. Individuals followed from birth to T1D showed ZnT8A as early as 2 years of age and increasing levels and prevalence persisting to disease onset. ZnT8A generally emerged later than GADA and IAA in prediabetes, although not in a strict order. The combined measurement of ZnT8A, GADA, IA2A, and IAA raised autoimmunity detection rates to 98% at disease onset, a level that approaches that needed to detect prediabetes in a general pediatric population. The combination of bioinformatics and molecular engineering used here will potentially generate other diabetes autoimmunity markers and is also broadly applicable to other autoimmune disorders.

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Mammalian zinc transporters: nutritional and physiologic regulation.

Louis Lichten, Robert J Cousins (2009)

Research advances defining how zinc is transported into and out of cells and organelles have increased exponentially within the past five years. Research has progressed through application of molecular techniques including genomic analysis, cell transfection, RNA interference, kinetic analysis of ion transport, and application of cell and animal models including knockout mice. The knowledge base has increased for most of 10 members of the ZnT family and 14 members of the Zrt-, Irt-like protein (ZIP) family. Relative to the handling of dietary zinc is the involvement of ZnT1, ZIP4, and ZIP5 in intestinal zinc transport, involvement of ZIP10 and ZnT1 in renal zinc reabsorption, and the roles of ZIP5, ZnT2, and ZnT1 in pancreatic release of endogenous zinc. These events are major factors in regulation of zinc homeostasis. Other salient findings are the involvement of ZnT2 in lactation, ZIP14 in the hypozincemia of inflammation, ZIP6, ZIP7, and ZIP10 in metastatic breast cancer, and ZnT8 in insulin processing and as an autoantigen in diabetes.

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Author and article information

Contributors

Zui Pan: zui.pan@uta.edu

Journal

Journal ID (nlm-ta): Acta Pharmacol Sin

Journal ID (iso-abbrev): Acta Pharmacol. Sin

Title: Acta Pharmacologica Sinica

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1671-4083

ISSN (Electronic): 1745-7254

Publication date (Electronic): 21 June 2018

Publication date (Print): July 2018

Volume: 39

Issue: 7

Pages: 1120-1132

Affiliations

ISNI 0000 0001 2181 9515, GRID grid.267315.4, College of Nursing and Health Innovation, , University of Texas at Arlington, ; Arlington, USA TX

Article

Publisher ID: 98

DOI: 10.1038/aps.2018.25

PMC ID: 6289396

PubMed ID: 29926844

SO-VID: 8508075a-6dfa-40a7-af5b-13bf104f317b

License:

This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

History

Date received : 15 December 2017

Date accepted : 28 February 2018

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ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: zinc homeostasis,zinc transporter (znt),zrt,irt-like protein (zip),metallothionein (mt),cardiovascular diseases,atherosclerosis,inflammation,ros

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ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: zinc homeostasis, zinc transporter (znt), zrt, irt-like protein (zip), metallothionein (mt), cardiovascular diseases, atherosclerosis, inflammation, ros

Zinc deficiency and cellular oxidative stress: prognostic implications in cardiovascular diseases

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Abstract

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Journal of Applied Pharmaceutical Science

Most cited references 100

A genome-wide association study identifies novel risk loci for type 2 diabetes.

The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes.

Mammalian zinc transporters: nutritional and physiologic regulation.

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