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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 #208706
Title: Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice

Author
item JIANG, YOUCHUN - UNIV OF LOUISVILLE KY
item REYNOLDS, COREY - UNIV OF LOUISVILLE KY
item XIAO, CHANG - UNIV OF LOUISVILLE KY
item FENG, WENKE - UNIV OF LOUISVILLE KY
item ZHOU, ZHANXIANG - UNIV OF LOUISVILLE KY
item RODRIGUEZ, WALTER - UNIV OF LOUISVILLE KY
item TYAGI, SURESH - UNIV OF LOUISVILLE KY
item EATON, JOHN - UNIV OF LOUISVILLE KY
item Saari, Jack
item KANG, Y - UNIV OF LOUISVILLE KY

Submitted to: Journal of Experimental Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/14/2007
Publication Date: 3/19/2007
Citation: Jiang, Y., Reynolds, C., Xiao, C., Feng, W., Zhou, Z., Rodriguez, W., Tyagi, S., Eaton, J.W., Saari, J.T., Kang, Y.J. 2007. Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice. Journal of Experimental Medicine. 204(3):657-666.

Interpretive Summary: If the heart is required to pump against a high pressure, it enlarges and can begin to fail. Because dietary copper deficiency can also lead to heart enlargement, we tested whether enlargement caused by high pressure can lead to reduced heart copper and if increasing dietary copper can counteract the effect of high pressure on the heart. Mice fed 6 parts per million of dietary copper, an amount regarded by rodent nutritionists as adequate, and subjected to constriction of the aorta to simulate pressure overload exhibited enlarged hearts and a reduction of heart copper concentration. The heart enlargement and reduction in heart copper were reversed when the mice were fed copper at 20 parts per million in the diet, which is not regarded as excessive. Further, we have found that this reversal of pathology by copper is related to a specific molecule responsible for transporting copper in the heart and to copper’s effect on blood vessel and heart growth factors. These findings suggest that when the heart is placed under stress the dietary requirement for copper increases.

Technical Abstract: Sustained pressure overload causes cardiac hypertrophy and the transition to heart failure. We show here that dietary supplementation with physiologically relevant levels of copper (Cu) reverses pre-established hypertrophic cardiomyopathy in the presence of pressure overload induced by ascending aortic constriction in mouse model. Sustained pressure overload leads to decreases in cardiac Cu and vascular endothelial growth factor (VEGF) levels along with suppression of myocardial angiogenesis. Cu supplementation replenishes cardiac Cu,increases VEGF, and promotes angiogenesis. Systemic administration of anti-VEGH antibody blunts Cu regression of hypertrophic cardiomyopathy. In cultured human cardiomyocytes, Cu chelator blocks insulin-like growth factor-1 (IGF-1)- or Cu-stimulated VEGF expression, which is antagonized by addition of excess Cu. Both IGF-1 and Cu activate hypoxia-inducible factor-1 alpha (HIF-1 alpha) and HIF-1 alpha gene silencing blocks IGF-1- or Cu-stimulated VEGF expression. HIF-1 alpha co-immunoprecipitates with Cu chaperone for superoxide dismutase-1 (CCS) and gene silencing of CCS, but not superoxide dismutase-1, prevents IGF-1- or Cu-induced HIF-1 alpha activation and VEGF expression. Therefore, dietary Cu supplementation improves the condition of hypertrophic cardiomyopathy at least in part through CCS-mediated HIF-1 alpha activation of VEGF expression and angiogenesis.