Enzymatic and non-enzymatic post-translational modifications linking diabetes and heart disease

Diabetes-related morbidity and mortality is evident in the increased prevalence of cardiovascular diseases and the high-risk of heart failure. Diabetic cardiomyopathy is a well-known complication of diabetes, and is defined as a ventricular dysfunction independent of coronary heart diseases and hypertension. The Framingham study firmly established an epidemiological link between diabetes and heart failure. Diabetes causes metabolic disturbances, cardiac fibrosis, endothelial and vascular smooth muscle cell dysfunctions, altered contractile performance, and arrhythmia. The underlying mechanisms of the adverse effects of diabetes on the heart remain poorly understood. However, it is certain that diabetic heart disease is a consequence of multiple factors including uncontrolled hyperglycemia, insulin resistance and dyslipidemia. Chronic hyperglycemia causes glucose toxicity, which mediates the detrimental effects of diabetes through the activation of a number of pathways, such as the polyol pathway, oxidative stress, mitochondrial dysfunction, activation of protein kinases, hexosamine biosynthesis pathway and non-enzymatic glycation reaction. The hexosamine biosynthesis pathway generates uridine diphosphateN-acetylglucosamine (UDP-GlcNAc), which is an activated precursor for both N-linked and O-linked glycosylation of proteins, and the substrate for b-O-linked GlcNAc (O-GlcNAc) modification of proteins (Figure 1). Recently, O-GlcNAc covalent modification of cardiac proteins has received considerable attention as a key factor in diabetic cardiac pathology. In contrast to non-enzymatic glycation reactions, O-GlcNAc glycosylation is a reversible and labile post-translational modification. After entering a cell, glucose is phosphorylated to glucose-6-phosphate (Figure 1). It is further metabolized during glycolysis to fructose-6-phosphate, which leads to accessory pathways of glucose metabolism; one such pathway is the hexosamine biosynthesis pathway. Under normal physiological conditions, approximately 5% of intracellular glucose enters the hexosamine biosynthesis pathway; however, its flux is upregulated in diabetic cardiomyocytes. The rate-limiting enzyme glutamine, fructose-6-phosphate aminotransferase (GFAT), converts fructose-6-phosphate to glucosamine-6-phosphate, which is then converted into UDP-GlcNAc and transferred onto target proteins by O-GlcNAc transferase (OGT). The enzyme, O-GlcNAcase, catalyzes the removal of the O-GlcNAc adduct from O-GlcNAcylated proteins (Figure 1). O-GlcNAcylation is reported to be involved in a number of cellular processes including signal transduction, protein–protein interactions, translation, protein degradation and gene expression