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. 2013 Mar 28;12:54.
doi: 10.1186/1475-2840-12-54.

Zinc Protects Against Diabetes-Induced Pathogenic Changes in the Aorta: Roles of Metallothionein and Nuclear Factor (Erythroid-Derived 2)-like 2

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Zinc Protects Against Diabetes-Induced Pathogenic Changes in the Aorta: Roles of Metallothionein and Nuclear Factor (Erythroid-Derived 2)-like 2

Xiao Miao et al. Cardiovasc Diabetol. .
Free PMC article

Abstract

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.

Figures

Figure 1
Figure 1
Preventive effect of Zn on diabetes-induced aortic pathological changes. The pathogenic changes of aortas were examined by H&E staining (A), and Sirius-red staining for collagen accumulation (B), followed with semi-quantitative analysis. Data were presented as means ± SD (n = 6). *, p < 0.05 vs. Corresponding Control; #, p < 0.05 vs. Corresponding DM. Bar = 50 μM.
Figure 2
Figure 2
Preventive effect of Zn on diabetes-induced aortic fibrosis. Aortic fibrosis was examined by immunohistochemical staining for the expression of CTGF (A), TGF-β1 (B) and Collagen IV (C), followed with semi-quantitative analysis. Data were presented as means ± SD (n = 6). *, p < 0.05 vs. Corresponding Control; #, p < 0.05 vs. Corresponding DM. Bar = 50 μM.
Figure 3
Figure 3
Preventive effect of Zn on diabetes-induced aortic inflammation. Aortic inflammation was examined by immunofluorescent staining for the expression of VCAM-1(A) (red) and immunohistochemical staining for the expression of PAI-1 (B), followed by semi-quantitative analysis. Data were presented as means ± SD (n = 6).*, p < 0.05 vs. Corresponding Control; #, p < 0.05 vs. Corresponding DM. Bar = 50 μM.
Figure 4
Figure 4
Preventive effect of Zn on diabetes-induced aortic TNF-α expression. Aortic expression of TNF-α was examined by real-time PCR for its mRNA level (A) and immunohistochemical staining for its protein expression in aortic tunica media (B for male and C for female), followed by semi-quantitative analysis (D for both male and female). Data were presented as means ± SD (n = 6).*, p < 0.05 vs. Corresponding Control; #, p < 0.05 vs. Corresponding DM. Bar = 50 μM.
Figure 5
Figure 5
Preventive effect of Zn on diabetes-induced aortic oxidative damage. The oxidative damage was examined by immunohistochemical staining for the accumulation of 4-HNE (A) and 3-NT (B), followed with semi-quantitative analysis. Data were presented as means ± SD (n = 6).*, p < 0.05 vs. Corresponding Control; #, p < 0.05 vs. Corresponding DM. Bar = 50 μM.
Figure 6
Figure 6
Diabetes induced aortic apoptosis and proliferation increased. The apoptotic cell was examined by TUNEL staining (A), followed with semi-quantitative analysis. And the proliferation of aortic tunica media was examined by immunohistochemical staining for ki-67 positive cells (B), followed with semi-quantitative analysis. Data were presented as means ± SD (n = 6).*, p < 0.05 vs. Corresponding Control; #, p < 0.05 vs. Corresponding DM. Bar = 50 μM.
Figure 7
Figure 7
Effects of Zn on aortic expression of Nrf2. Aortic expression of Nrf2 was examined by real-time PCR for its mRNA level (A) and immunohistochemical staining for its protein expression (red) in aortic tunica media (B for male and C for female) with semi-quantitative analysis (D for both male and female).Data were presented as means ± SD (n = 6).*, p < 0.05 vs. Corresponding Control; #, p < 0.05 vs. Corresponding DM. Bar = 50 μM.
Figure 8
Figure 8
Effects of Zn on aortic expression of Nrf2 downstream genes. Aortic expression of Nrf2 down-stream genes NQO-1 expression was examined by real-time PCR at mRNA level (A) and immunohistochemical staining for protein expression in aortic tunica media (B for male and C for female) with semi-quantitative analysis (D for both male and female).Data were presented as means ± SD (n = 6).*, p < 0.05 vs. Corresponding Control; #, p < 0.05 vs. Corresponding DM. Bar = 50 μM.
Figure 9
Figure 9
Effects of Zn on aortic expression of MT. Aortic expression of MT expression was examined by real-time PCR for its mRNA level (A) and immunohistochemical staining for its protein expression in aortic tunica media (B for male and C for female), followed with semi-quantitative analysis (D for both male and female).Data were presented as means ± SD (n = 6).*, p < 0.05 vs. Corresponding Control; #, p < 0.05 vs. Corresponding DM. Bar = 50 μM.

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