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Published on: April 21, 2010
Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice
Youchun Jiang1, Corey Reynolds, Chang Xiao
1Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Insights
Dietary copper (Cu) supplementation reverses pressure overload-induced cardiac hypertrophy in mice. This occurs by increasing vascular endothelial growth factor (VEGF) and promoting blood vessel growth, offering a potential therapy for heart failure.
Area of Science:
- Cardiovascular Biology
- Nutritional Biochemistry
- Molecular Cardiology
Background:
- Sustained pressure overload leads to cardiac hypertrophy and heart failure.
- This condition is associated with reduced cardiac copper (Cu) and vascular endothelial growth factor (VEGF) levels, impairing myocardial angiogenesis.
- Current treatments for pressure overload-induced heart disease are limited.
Purpose of the Study:
- To investigate the therapeutic potential of dietary copper (Cu) supplementation in reversing established pressure overload-induced hypertrophic cardiomyopathy.
- To elucidate the molecular mechanisms underlying Cu's effects on cardiac function and angiogenesis.
Main Methods:
- Utilized a mouse model of ascending aortic constriction to induce pressure overload and cardiac hypertrophy.
- Administered physiologically relevant levels of dietary copper (Cu) to supplemented mice.
- Measured cardiac Cu, VEGF levels, and assessed myocardial angiogenesis.
- Employed anti-VEGF antibodies and gene silencing techniques in cultured human cardiomyocytes and in vivo.
Main Results:
- Dietary Cu supplementation reversed pre-existing hypertrophic cardiomyopathy in mice, even with continued pressure overload.
- Cu replenishment increased cardiac VEGF levels and promoted myocardial angiogenesis.
- Systemic anti-VEGF antibody administration partially blocked the beneficial effects of Cu.
- In vitro studies demonstrated that Cu and insulin-like growth factor (IGF)-1 activate hypoxia-inducible factor (HIF)-1alpha, leading to VEGF expression.
Conclusions:
- Dietary copper (Cu) supplementation effectively reverses pressure overload-induced hypertrophic cardiomyopathy.
- The mechanism involves Cu-mediated activation of the copper chaperone for superoxide dismutase-1 (CCS) and hypoxia-inducible factor (HIF)-1alpha, enhancing VEGF expression and angiogenesis.
- Cu supplementation represents a promising therapeutic strategy for heart failure associated with cardiac hypertrophy.
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 preestablished hypertrophic cardiomyopathy caused by pressure overload induced by ascending aortic constriction in a mouse model. The reversal occurs in the continued presence of pressure overload. 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-VEGF antibody blunts Cu regression of hypertrophic cardiomyopathy. In cultured human cardiomyocytes, Cu chelation blocks insulin-like growth factor (IGF)-1- or Cu-stimulated VEGF expression, which is relieved by addition of excess Cu. Both IGF-1 and Cu activate hypoxia-inducible factor (HIF)-1alpha and HIF-1alpha gene silencing blocks IGF-1- or Cu-stimulated VEGF expression. HIF-1alpha coimmunoprecipitates with a Cu chaperone for superoxide dismutase-1 (CCS), and gene silencing of CCS, but not superoxide dismutase-1, prevents IGF-1- or Cu-induced HIF-1alpha activation and VEGF expression. Therefore, dietary Cu supplementation improves the condition of hypertrophic cardiomyopathy at least in part through CCS-mediated HIF-1alpha activation of VEGF expression and angiogenesis.
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