Zinc Protects Against Diabetes-induced Pathogenic Changes in the Aorta

Roles of Metallothionein and Nuclear Factor (Erythroid-Derived 2)-Like 2

Xiao Miao; Yonggang Wang; Jian Sun; Weixia Sun; Yi Tan; Lu Cai; Yang Zheng; Guanfang Su; Quan Liu; Yuehui Wang


Cardiovasc Diabetol. 2013;12(54) 

In This Article

Abstract and Introduction


Background: Cardiovascular diseases remain a leading cause of the mortality world-wide, which is related to several risks, including the life style change and the increased diabetes prevalence. The present study was to explore the preventive effect of zinc on the pathogenic changes in the aorta.

Methods: A genetic type 1 diabetic OVE26 mouse model was used with/without zinc supplementation for 3 months. To determine gender difference either for pathogenic changes in the aorta of diabetic mice or for zinc protective effects on diabetes-induced pathogenic changes, both males and females were investigated in parallel by histopathological and immunohistochemical examinations, in combination of real-time PCR assay.

Results: Diabetes induced significant increases in aortic oxidative damage, inflammation, and remodeling (increased fibrosis and wall thickness) without significant difference between genders. Zinc treatment of these diabetic mice for three months completely prevented the above pathogenic changes in the aorta, and also significantly up-regulated the expression and function of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a pivotal regulator of anti-oxidative mechanism, and the expression of metallothionein (MT), a potent antioxidant. There was gender difference for the protective effect of zinc against diabetes-induced pathogenic changes and the up-regulated levels of Nrf2 and MT in the aorta.

Conclusions: These results suggest that zinc supplementation provides a significant protection against diabetes-induced pathogenic changes in the aorta without gender difference in the type 1 diabetic mouse model. The aortic protection by zinc against diabetes-induced pathogenic changes is associated with the up-regulation of both MT and Nrf2 expression.


Cardiovascular disease is a leading cause of mortality. The causes of cardiovascular diseases are multifaceted, including environmental pollution[1,2] and life style changes such as the lack of physical activity and the increased intake of Western foods that include over-nutrition and trace elemental dyshomeostasis.[3,4]

Cardiovascular diseases are sex difference. For instance, men have an increased incidence and severity of most cardiovascular diseases, including atherosclerosis, myocardial infarction, dilated cardiomyopathy, and heart failure, with the exception of hypertension that is higher in women.[1–4] However, the preventive effects that make females with a low incidence of cardiovascular diseases compared to males were diminished under diabetic conditions.[5] This may be because the vascular gender peculiarities. For instance, animal studies showed that endothelium-intact thoracic aortic rings from age-matched male and female Sprague–Dawley rats were responsive to insulin, by showing the relaxation. The hyperglycemia was found able to inhibit the response of aortic rings to insulin and apparently the female vascular endothelium is more sensitive to the toxic effect of hyperglycemia than the male vascular endothelium.[6] Human studies also supports the concept that women who progressed from normoglycemia to pre-diabetes or hyperglycemia have a greater endothelial dysfunction, more hypertension, and a greater degree of fibrinolysis/thrombosis than men.[7] However, mechanisms by which diabetes impacts more female than male remain unclear.[6,7]

Zinc (Zn) is one of the important essential trace metals that are required for many cell events. Zn is not only an important nutrient, cofactor of numerous enzymes and transcription factors, but also acts as intracellular signaling mediator.[8] So far, more than 300 catalytically active Zn metalloproteinase and more than 2000 Zn dependent transcription factors have been recognized. Therefore, Zn dyshomeostasis such as Zn deficiency is associated with various chronic pathogeneses, including vascular diseases.[9] For instance, Zn deficiency in endothelial cells potentiates the inflammatory response mediated by certain lipids and cytokines, possibly via mechanisms associated with increased cellular oxidative stress;[10,11] however, Zn supplementation protects vascular system from oxidative damage.[12,13]

One of the mechanisms by which Zn supplementation protects vascular system from oxidative damage may include the up-regulation of NF-E2-related factor 2 (Nrf2) expression and function.[14,15] The antioxidant responsive element (ARE) is a cis-acting regulatory element of genes encoding phase II detoxification enzymes and antioxidant proteins, such as NAD(P)H: quinone oxidoreductase 1 (NQO-1), HO-1, glutathione S-transferases, and glutamate-cysteine ligase. Nrf2 regulates a wide array of ARE-driven genes in various cell types. The DNA binding sequence of Nrf2 and ARE sequence are very similar so that Nrf2 binds to the ARE sites leading to up-regulation of downstream genes. Therefore, the Nrf2-ARE pathway is important in the cellular antioxidant defense system to protect the cell and tissue from oxidative stress, including diabetes.[16,17]

Another important potential mechanism may be the induction of metallothionein (MT) expression.[18,19] MTs are cysteine-rich metal-binding proteins with several biological roles including antioxidant property. We and others have indicated the significant protection of MT against diabetes and diabetes-induced cardiovascular damage.[19–22] MT is ubiquitously expressed in mammalian tissues and also highly inducible by a variety of reagents such as Zn; therefore, the protective effect of Zn supplementation on diabetic heart and kidney was noticed before.[18,23,24]

Therefore, the present study was first to explore whether diabetes-induced pathogenic changes in the aorta can be prevented by Zn supplementation, and to compare whether there is a difference between female and male for the preventive effect of Zn supplementation on diabetes-induced pathogenic changes in the aorta. Then the possible mechanisms by which Zn prevents the aorta from diabetes-induced pathogenic changes were explored by analyzing Nrf2's expression and function, and also MT expression.