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ARS Home » Plains Area » Grand Forks, North Dakota » Grand Forks Human Nutrition Research Center » Healthy Body Weight Research » Research » Publications at this Location » Publication #133302
Title: Changes in copper and zinc status and response to dietary copper deficiency in metallothionein-overexpressing transgenic mouse heart

Author
item KANG, Y - UNIV OF LOUISVILLE
item JIANG, YOUCHUN - UNIV OF LOUISVILLE
item Saari, Jack

Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/16/2006
Publication Date: 11/1/2007
Citation: Kang, Y.J., Jiang, Y., Saari, J.T. 2007. Changes in copper and zinc status and response to dietary copper deficiency in metallothionein-overexpressing transgenic mouse heart. Journal of Nutritional Biochemistry. 18(11):714-718.

Interpretive Summary: Dietary copper deficiency causes heart enlargement, reduced heart function and, eventually, heart failure, in laboratory animals. It has been suggested that this heart pathology is caused by oxidative stress, an attack on heart structure by free radicals that are produced by the body's normal metabolic processes. We have previously shown that genetically altering mice to produce elevated amounts of heart metallothionein, a protein that destroys free radicals, inhibits the deleterious heart changes. To further test the cause of this protective effect of metallothionein, we examined trace element changes in the heart in response to genetically elevated metallothionein and dietary copper deficiency. We found that heart zinc concentration was significantly elevated, in parallel with elevation of metallothionein, and that copper deficiency didn't greatly affect this change in zinc, which suggests that the protective effect of metallothionein on copper-deficient hearts may be caused by zinc. This study is important because it contributes to an understanding of the molecular basis for altered heart function in copper deficiency. It indicates that copper deficiency may be used as an experimental model for studying other types of heart failure and it supports the view that elevation of metallothionein may be a possible therapeutic approach in treating heart failure.

Technical Abstract: Previous studies have shown that metallothionein (MT) inhibits myocardial apoptosis induced by dietary copper restriction and that this inhibition is related to the antioxidant action of MT. However, the mechanism of action of MT in vivo is not known. Recent studies have suggested that zinc release from MT under oxidative stress likely mediates the antioxidant action. The present study was undertaken to determine alterations of zinc and other minerals in the cardiac-specific, MT-overexpressing, transgenic (MT-TG) mouse heart in order to determine the link between the metabolism of zinc as well as other minerals and the antioxidant action of MT in vivo. In addition, differential responses of the MT-TG relative to wild-type (WT) mouse hearts to dietary copper restriction were also determined. Dams of both MT-TG pups and WT littermates were fed copper-adequate or copper-deficient diet starting on the fourth day post delivery and the weanling mice were continued on the dams' diets until they were sacrificed. The foremost change in mineral metabolism in the MT-TG mouse heart was a 2.5-fold elevation of zinc, although copper concentrations were also significantly increased. Dietary copper restriction significantly decreased copper concentrations to the same extent in both MT-TG and WT mouse hearts, and slightly decreased zinc concentrations along with a similar decrease in MT concentration in the MT-TG mouse heart. Moreover, copper deficiency-induced heart hypertrophy was significantly inhibited in the MT-TG mice, as determined by heart weight and the ratio of heart weight to body weight. Copper deficiency-induced loss of body weight, but not suppressed serum ceruloplasmin or hepatic Cu,Zn-SOD activities, was also inhibited in the MT-TG mice. This study thus suggests that zinc elevation in the heart is likely involved in the MT protection against copper-deficiency-induced oxidative stress.