Myocardial regeneration is the key to the functional recovery of ischemic heart. Angiogenesis plays a pivotal role in myocardial regeneration by resetting a rejuvenation microenvironment under ischemic conditions. Hypoxia-inducible factor 1 (HIF-1) is the predominant transcription factor in the regulation of angiogenesis. In prolonged myocardial infarction, HIF-1α, the critical subunit of HIF-1, is accumulated in the infarcted myocardium, but fails to activate angiogenesis, suggesting a missing of a critical factor in the HIF-1 regulation of angiogenesis. Copper is involved in multiple steps of HIF-1 regulation of target gene expression. However, copper is deprived during myocardial ischemic injury, leading to deactivation of HIF-1-regulated angiogenesis. Multiple approaches are applied to increasing copper availability in the ischemic heart, effectively reactivating transcription of HIF-1 target angiogenic genes. Copper-induced angiogenesis thus reconstructs the conduit for the transduction of tissue injury signaling, recruitment of tissue repair materials such as stem cells, and the homing of stem cells, leading to the promotion of myocardial regeneration. Thus, copper promotes myocardial regeneration through reactivation of HIF-1-regulated angiogenesis. This would constitute an alternative therapeutic approach to ischemic heart disease.

Impact statement

Copper promotes angiogenesis, but the mechanistic insights have not been fully elucidated until recently. In addition, the significance of copper promotion of angiogenesis in myocardial regeneration was increasingly revealed. Copper critically participates in the regulation of hypoxia-inducible factor 1 (HIF-1) of angiogenic gene expression. Interestingly, myocardial ischemia causes copper efflux from the heart, leading to suppression of angiogenesis, although HIF-1α, the critical subunit of HIF-1, remains accumulated in the ischemic myocardium. Strategies targeting copper specific delivery to the ischemic myocardium lead to selective activation of HIF-1-regulated angiogenic gene expression. Vascularization of the ischemic myocardium re-establishes the tissue injury microenvironment, and rebuilds the conduit for communication between the tissue injury signals and the remote regenerative responses including stem cells. This process promotes myocardial regeneration. Thus, a simple and effective copper supplementation to the ischemic myocardium would become a novel therapeutic approach to the treatment of patients with ischemic heart diseases.

中文翻译：

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铜促进心肌再生。

心肌再生是缺血心脏功能恢复的关键。通过在缺血条件下恢复嫩化微环境，血管生成在心肌再生中起关键作用。缺氧诱导因子1（HIF-1）是调节血管生成的主要转录因子。在长时间的心肌梗塞中，HIF-1的关键亚基HIF-1α积累在梗塞的心肌中，但无法激活血管生成，提示缺少HIF-1调节血管生成的关键因素。铜参与靶基因表达的HIF-1调节的多个步骤。但是，心肌缺血性损伤期间铜被剥夺，导致HIF-1调节的血管生成失活。多种方法可用于增加缺血心脏中的铜利用率，有效激活HIF-1靶血管生成基因的转录。铜诱导的血管生成因此重建了用于传导组织损伤信号传导，募集组织修复材料（例如干细胞）和干细胞归巢的导管，从而促进了心肌再生。因此，铜通过重新激活HIF-1调节的血管生成促进心肌再生。这将构成缺血性心脏病的替代治疗方法。铜通过激活HIF-1调节的血管生成来促进心肌再生。这将构成缺血性心脏病的替代治疗方法。铜通过激活HIF-1调节的血管生成来促进心肌再生。这将构成缺血性心脏病的替代治疗方法。

影响陈述

铜促进血管生成，但是直到最近才完全阐明机理的见解。此外，越来越多地揭示了铜促进心肌再生中血管生成的重要性。铜关键参与血管生成基因表达的缺氧诱导因子1（HIF-1）的调节。有趣的是，尽管HIF-1的关键亚基HIF-1α仍积累在缺血心肌中，但心肌缺血会引起心脏铜流出，从而抑制血管生成。针对铜特异性递送至缺血心肌的策略导致选择性激活HIF-1调节的血管生成基因表达。缺血性心肌的血管化重建了组织损伤的微环境，并重建用于组织损伤信号与包括干细胞在内的远程再生反应之间通信的管道。该过程促进心肌再生。因此，对缺血性心肌进行简单有效的铜补充将成为治疗缺血性心脏病患者的一种新颖的治疗方法。