Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 204, Issue 3, Pages 657-666Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20061943
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Funding
- NHLBI NIH HHS [R01 HL063760, R01 HL059225, HL63760, HL59225] Funding Source: Medline
- NIAAA NIH HHS [R01 AA014623] Funding Source: Medline
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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)-1 alpha and HIF-1 alpha gene silencing blocks IGF-1- or Cu-stimulated VEGF expression. HIF-1 alpha 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-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.
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