Ischemia-induced copper loss and suppression of angiogenesis in the pathogenesis of myocardial infarction.
Myocardial ischemia is a primary cause for the loss of vital components such as cardiomyocytes in the heart, leading to myocardial infarction and eventual cardiac dysfunction or heart failure. Suppressed angiogenesis plays a determinant role in the pathogenesis of myocardial infarction. In response to myocardial ischemia, hypoxia-inducible factor-1α and 2α (HIF-1α and HIF-2α) accumulate in cardiomyocytes and other cell types. This would up-regulate the expression of genes involved in angiogenesis such as vascular endothelial growth factor (VEGF); however, it is often observed that the angiogenic capacity is suppressed rather than enhanced. Ischemic toxicity, which has not been fully recognized, is highly responsible for the compromised angiogenic capacity. One of the toxic effects resulting from myocardial ischemia is the loss of copper content in the heart. Although the reason for this loss has not been elucidated, the essential role of copper in the regulation of HIF-1 transcriptional activity has been described. Copper does not affect the accumulation of HIF-1α in the cell, but is required for the HIF-1 transcriptional complex formation and its interaction with the hypoxia-responsive element in target genes. Copper supplementation can stimulate the transcriptional activity of HIF-1 and restore angiogenic capacity, leading to increased capillary density in the heart. The recognition of ischemic toxicity and the effort to overcome the toxic effect would help develop alternative approaches in the treatment of ischemic heart disease.
Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, People's Republic of China.
Weihong
W
He
Y
Y
James Kang
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D003300:Copper / Q000172:deficiency* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D017202:Myocardial Ischemia / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000150:complications* / Q000378:metabolism* / Q000517:prevention & control; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D003300:Copper; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human