Ischemia-induced Copper Loss and Suppression of Angiogenesis in the Pathogenesis of Myocardial Infarction

Abstract

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.

Association between copper levels and myocardial infarction: a meta-analysis

“…Kok et al (1988) show that the adjusted risk of death from cardiovascular disease was about four times higher for subjects in the highest serum Cu quintile compared with those with normal levels, indicating that high serum Cu is associated with the mortality of cardiovascular disease. Although there is not necessarily a direct causeeffect relationship between the development of MI and Cu concentration, it is frequently assumed that Cu is MI risk factor (Gomez et al, 2000;He & James Kang, 2013). Researchers have found that high dietary Cu increased all lipid classes and fatty acid unsaturation (palmitoleic, oleic, linoleic acids), decreased stearic acid in phosphatidylcholine and phosphatidylethanolamine of heart (Jenkins & Kramer, 1989).…”

Deficient Zinc Levels and Myocardial Infarction

“…Trace elements are being increasingly recognized as essential mediators of the development and progression of MI [3,4]. Although there is no necessarily a direct cause-effect relationship between the development of MI and trace elements status, it is generally believed that the disturbances of them, such as zinc (Zn) and copper (Cu), are risk factors for MI [5,6].…”

Mitochondrial Aldehyde Dehydrogenase 2 Regulates Revascularization in Chronic Ischemia

“…This is distinct from vasculogenesis, and is responsible for majority of blood vessel growth during development and in pathological conditions. 39,40 A hypoxia-inducible program, driven by HIF-1α, renders endothelial cells responsive to angiogenic signals. 41,42 Normally, when sufficient oxygen is available, HIF-1α may be hydroxylated by the oxygen-sensing enzymes named proteins PHD1-3.…”