An Emerging Role of Defective Copper Metabolism in Heart Disease

Abstract

Copper is an essential trace metal element that significantly affects human physiology and pathology by regulating various important biological processes, including mitochondrial oxidative phosphorylation, iron mobilization, connective tissue crosslinking, antioxidant defense, melanin synthesis, blood clotting, and neuron peptide maturation. Increasing lines of evidence obtained from studies of cell culture, animals, and human genetics have demonstrated that dysregulation of copper metabolism causes heart disease, which is the leading cause of mortality in the US. Defects of copper homeostasis caused by perturbed regulation of copper chaperones or copper transporters or by copper deficiency resulted in various types of heart disease, including cardiac hypertrophy, heart failure, ischemic heart disease, and diabetes mellitus cardiomyopathy. This review aims to provide a timely summary of the effects of defective copper homeostasis on heart disease and discuss potential underlying molecular mechanisms.

Association between Blood Copper Levels and the Incidence of Ischemic Heart Disease

“…Copper plays a role in maintaining the activity of copper-dependent proteins, such as cytochrome c oxidase (CCO), superoxide dismutase-1 or -3 (SOD1/3), metallothionein (MT), ceruloplasmin (CP), and lysyl oxidase (LOX), which are proteins essential in the regulation of oxidative phosphorylation, iron mobilization, antioxidant defense, and cross-linking of connective tissue in the heart. Impaired copper metabolism, including copper deficiency and disorders of copper companion, copper transporter, or copper-binding protein causes cardiac dysfunction, myopathy, and an increased risk of death [16]. DiNicolatonio et al also concluded that there is a relationship between copper deficiency and the incidence of ischemic heart disease [37].…”

“…Copper is an essential trace metal micronutrient, less abundant than other metals such as iron and zinc, but widely utilized as a catalytic or structural cofactor by enzymes and proteins that are highly relevant to cardiac physiology and pathology. Copper regulates various important biological processes, including mitochondrial oxidative phosphorylation, iron mobilization, connective tissue crosslinking, antioxidant defense, melanin synthesis, blood clotting, and neuron peptide maturation [16]. It has long been known that copper is essential for cardiac metabolism and function [17], [18], [19].…”

The Molecular Mechanisms of Defective Copper Metabolism in Diabetic Cardiomyopathy

“…Heart failure in diabetes may thus be explained in part by defective distribution of the two copper valence states and the myocardial damage that ensues [ 190 ]. A meta-analysis including 1504 subjects indicated that serum copper levels were significantly increased in patients with heart failure [ 191 ].…”

Plasma Metallomics Reveals Potential Biomarkers and Insights into the Ambivalent Associations of Elements with Acute Myocardial Infarction

“…Firstly, for Cu, Cu depletion/deficiency was more commonly reported as a risk factor of the CVDs and even a leading cause of CHD particularly. [50][51][52] Cu plays essential roles in many biological processes (e.g., co-factor for many antioxidant enzymes, involvement in glycation, possible involvement in cytochrome and mitochondria activity, regulation of blood vessels' response to inflammatory stimuli), and its deficiency could dysregulate these processes, leading to the promotion of disease. 50,51 However, there has also been contradicting reports on elevated circulating Cu found in CHD patients in large-scale studies from the USA and Finland, as well as in a smaller study in Iran.…”