Acquired copper imbalance in diabetes-induced cardiac disease: Molecular mechanisms and reversibility

Abstract

Diabetes is a metabolic disorder characterised by chronic hyperglycaemia, which results from disruption of several glucose-control mechanisms. In diabetic patients, it is well established that prolonged hyperglycaemia increases the risk of the cardiovascular complications, which are responsible for up to 80% of deaths and are the leading cause of the morbidity and mortality in T2DM. Clinical studies on diabetic patients have shown that chronic hyperglycaemia can disrupt myocardial copper balance and cause elevated serum copper levels, particularly in those patients with cardiovascular complications. It has also been shown that copper imbalance in the myocardium can be directly or indirectly involved in the pathogenesis of diabetes-induced cardiovascular disease. Recent studies from our group have shown that chronic treatment with a divalent Cu(II)-selective chelator, TETA, can ameliorate diabetes-induced disturbances in the regulation of copper homeostasis, and improve the structure and function of the heart in diabetic rats and humans. In this thesis, I have examined the interplay of hyperglycaemia and copper levels on cardiomyocyte structure and function in both a cellular and an animal model. It was found that the copper balance in cardiomyocytes was altered by chronic hyperglycaemia, which elicited decreased cellular copper levels and increased copper sensitivity compared to controls. Based on the results, I have concluded that chronic hyperglycaemia-induced copper imbalance could be due to changes in the intracellular copper-transport pathways, with genes involved in antioxidant mechanisms and the mitochondrial pathway found to be suppressed in cardiomyocytes cultured with high glucose. In the STZ-induced diabetic rat model, some of these abnormalities were also found in diabetic myocardium. In this thesis several of the abnormalities found in diabetic myocardium have been shown to be ameliorated with chronic TETA treatment. Although the mechanisms of drug action are not fully understood, we hypothesise that TETA treatment can improve cardiac function in the diabetic heart through the binding of excess free copper in the myocardium, which can lower copper-mediated oxidative stress and restore copper balance in the diabetic heart. These mechanisms can prevent further damage occurring and allow innate regenerative processes to take place in the myocardium to restore the structure and function of the diabetic heart.