Copper promotion of myocardial regeneration

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.