title: Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice.
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.
authors.affiliation: Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Youchun
authors.initials: Y
authors.lastname: Jiang
authors.forename: Corey
authors.initials: C
authors.lastname: Reynolds
authors.forename: Chang
authors.initials: C
authors.lastname: Xiao
authors.forename: Wenke
authors.initials: W
authors.lastname: Feng
authors.forename: Zhanxiang
authors.initials: Z
authors.lastname: Zhou
authors.forename: Walter
authors.initials: W
authors.lastname: Rodriguez
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Tyagi
authors.forename: John W
authors.initials: JW
authors.lastname: Eaton
authors.forename: Jack T
authors.initials: JT
authors.lastname: Saari
authors.forename: Y James
authors.initials: YJ
authors.lastname: Kang
mesh_terms: D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000178:diet therapy* / Q000209:etiology*; D002478:Cells, Cultured; D002908:Chronic Disease; D003300:Copper / Q000627:therapeutic use*; D019587:Dietary Supplements; D004195:Disease Models, Animal; D006801:Humans; D006973:Hypertension / Q000150:complications* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D003300:Copper