Role of copper in angiogenesis and its medicinal implications.
Role of copper in angiogenesis and its medicinal implications.
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DOI：
10.2174/092986709787846622
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发表时间：
2009-03
影响因子：
4.1
通讯作者：
Huiqi Xie;Y. J. Kang
中科院分区：
文献类型：
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作者：
Huiqi Xie;Y. J. Kang
铜促进血管生成的研究已经有二十多年的历史，但铜的作用机制直到最近才被探索出来。铜刺激参与血管形成和成熟的因子，如血管内皮生长因子（VEGF），是其血管生成作用的主要原因。铜是激活缺氧诱导因子-1 （HIF-1）所必需的，HIF-1是调节VEGF表达的主要转录因子。铜通过一个铜伴侣体被超氧化物歧化酶-1转运到细胞核中。铜是HIF-1与靶基因的缺氧反应元件相互作用所必需的，并确保HIF-1转录复合物的形成，从而激活包括VEGF在内的靶基因的表达。另一方面，过量的铜可以稳定HIF-1 α， HIF-1的限速成分，导致其在细胞质中积累，从而激活HIF-1。铜在VEGF生成中的重要作用使其涉及抗血管生成治疗，例如铜螯合剂在癌症治疗中的应用。然而，血管生成的抑制参与心脏肥厚的进展及其向心力衰竭的过渡，因此补充铜可改善肥厚性心脏病的病情。这种铜在癌症治疗和心脏肥厚中的影响的困境要求在对不同疾病实施铜操作疗法之前对患者的状况进行全面的了解。在这种情况下，对铜代谢变化的诊断以及组织特异性铜操作的发展将极大地造福于铜操作治疗的患者。
Copper promotion of angiogenesis has been known for more than two decades, but the mechanism of action of copper has not been explored until recently. Copper stimulation of factors involved in vessel formation and maturation, such as vascular endothelial growth factor (VEGF), is mainly responsible for its angiogenesis effect. Copper is required for the activation of hypoxia-inducible factor-1 (HIF-1), a major transcription factor regulating the expression of VEGF. Copper would be transported into nucleus by a copper chaperon for superoxide dismutase-1. Copper is required for HIF-1 interaction with the hypoxia-responsive element of the target genes and ensures the formation of HIF-1 transcriptional complex, thus activating the expression of target genes including VEGF. On the other hand, excess copper can stabilize HIF-1alpha, the rate-limiting component of HIF-1, leading to its accumulation in cytoplasm and thus HIF-1 activation. The essential role of copper in production of VEGF makes it implicated in anti-angiogenesis therapy, such as the application of copper chelators in cancer therapy. However, suppression of angiogenesis is involved in the progression of heart hypertrophy and its transition to heart failure, therefore copper supplementation improves hypertrophic heart disease conditions. This dilemma of copper implications in cancer therapy and heart hypertrophy dictates a comprehensive understanding of a patient's condition before an implementation of copper manipulation therapy for different diseases. In this context, a development of diagnosis for copper metabolic changes as well as a tissue-specific copper manipulation would greatly benefit patients with an implication of copper manipulation therapy.