Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice.
Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice.
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饮食铜补充剂逆转小鼠慢性压力超负荷引起的肥厚性心肌病。
DOI：
10.1084/jem.20061943
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发表时间：
2007-03-19
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持续的压力超负荷导致心脏肥大并转变为心力衰竭。我们在这里表明，饮食补充生理相关水平的铜（Cu）逆转预先建立的肥厚性心肌病引起的升主动脉缩窄引起的压力超负荷小鼠模型。在持续存在压力过载的情况下发生反转。持续的压力超负荷导致心脏Cu和血管内皮生长因子（VEGF）水平降低，同时沿着心肌血管生成抑制。补充铜可降低心脏铜含量，增加VEGF，促进血管生成。全身给予抗VEGF抗体可减缓肥厚型心肌病的Cu消退。在培养的人心肌细胞中，铜螯合阻断胰岛素样生长因子（IGF）-1-或铜刺激的VEGF表达，这是通过添加过量的铜缓解。IGF-1和Cu均激活缺氧诱导因子（HIF）-1 α，并且HIF-1 α基因沉默阻断IGF-1或Cu刺激的VEGF表达。HIF-1 α与超氧化物歧化酶-1（CCS）的Cu分子伴侣共免疫沉淀，并且CCS的基因沉默（而非超氧化物歧化酶-1）阻止IGF-1或Cu诱导的HIF-1 α活化和VEGF表达。因此，膳食铜补充剂至少部分通过CCS介导的HIF-1 α激活VEGF表达和血管生成来改善肥厚型心肌病的状况。
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)-1α and HIF-1α gene silencing blocks IGF-1– or Cu-stimulated VEGF expression. HIF-1α 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-1α activation and VEGF expression. Therefore, dietary Cu supplementation improves the condition of hypertrophic cardiomyopathy at least in part through CCS-mediated HIF-1α activation of VEGF expression and angiogenesis.