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Title: METALLOTHIONEIN INHIBITS MYOCARDIAL APOPTOSIS IN COPPER-DEFICIENT MICE: ROLE OF ATRIAL NATRIURETIC PEPTIDE

Author
item KANG, Y - UNIVERSITY OF LOUISVILLE
item ZHOU, ZHAN-XIANG - UNIVERSITY OF LOUISVILLE
item WU, HUIYUN - UNIVERSITY OF LOUISVILLE
item WANG, GUANG-WU - UNIVERSITY OF LOUISVILLE
item Saari, Jack
item KLEIN, JON - UNIVERSITY OF LOUISVILLE

Submitted to: Laboratory Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/1/2000
Publication Date: 5/1/2000
Citation: Kang, Y.J., Zhou, Z.X., Wu, H., Wang, G.W., Saari, J.T., Klein, J.B. 2000. Metallothionein inhibits myocardial apoptosis in copper-deficient mice: Role of atrial natriuretic peptide. Laboratory Investigation. 80:745-757.

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, attack on heart structure by free radicals that are produced by the body's normal metabolic processes. To test this hypothesis, hearts of mice were genetically altered to produce abnormally high amounts of a chemical, metallothionein, that acts to destroy free radicals. When fed copper- deficient diets, mice with high metallothionein in their hearts showed reduced heart enlargement compared to mice that contained normal metallothionein in their hearts. Additional study showed that metallothionien-containing hearts were also protected against the heart failure caused by copper deficiency, as indicated by reduced production of an abnormal protein and by a test that estimates rate of cell death. 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: Dietary copper (Cu) restriction causes heart hypertrophy in animal models. Several studies have indicated that this cardiomyopathy is mediated by oxidative stress. Metallothionein (MT), a low molecular weight and cysteine rich protein, functions as an antioxidant. We therefore hypothesized that MT would inhibit Cu deficiency-induced heart hypertrophy. We used a transgenic mouse model that overexpresses MT specifically in the heart. Dams of transgenic pups and non-transgenic littermates were fed Cu-adequate or Cu-deficient diet starting on the fourth day post delivery and weanling mice were continued on the dams' diets until sacrificed. Heart hypertrophy developed in Cu-deficient pups by the fourth week of the combined pre- and post- weaning feeding and aggressively progressed until the end of the experiment (6 wks). MT overexpression did not prevent the occurrence of heart hypertrophy, but inhibited its progression, which correlated with suppression of cardiac lipid peroxidation by MT. Myocardial apoptosis and atrial natriuretic peptide (ANP) production were also detected in heart ventricles of non- transgenic Cu-deficient mice; these effects were significantly suppressed in transgenic Cu-deficient mice. Measurement of apoptosis by TUNEL assay and Annexin V-FITC confocal microscopy in primary cultures of cardiomyocytes revealed that ANP was largely responsible for the myocyte apoptosis and that MT inhibited ANP-induced apoptosis. The data demonstrate that elevation of MT in the heart inhibits oxidative injury and suppresses the progression of heart hypertrophy in Cu deficiency and suggest that MT inhibits the transition from heart hypertrophy to failure by suppressing apoptosis through inhibition of cardiac ANP production.