US EPA

7470784 

Journal Article 

Insights into the role of maladaptive hexosamine biosynthesis and O-GlcNAcylation in development of diabetic cardiac complications 

Qin, CX; Sleaby, R; Davidoff, AJ; Bell, JR; De Blasio, MJ; Delbridge, LM; Chatham, JC; Ritchie, RH 

2017 

1 

Pharmacological Research
ISSN: 1043-6618
EISSN: 1096-1186 

Academic Press 

116 

45-56 

English 

10.1016/j.phrs.2016.12.016 

Diabetes mellitus significantly increases the risk of heart failure, independent of coronary artery disease. The mechanisms implicated in the development of diabetic heart disease, commonly termed diabetic cardiomyopathy, are complex, but much of the impact of diabetes on the heart can be attributed to impaired glucose handling. It has been shown that the maladaptive nutrient-sensing hexosamine biosynthesis pathway (HBP) contributes to diabetic complications in many non-cardiac tissues. Glucose metabolism by the HBP leads to enzymatically-regulated, O-linked attachment of a sugar moiety molecule, β-N-acetylglucosamine (O-GlcNAc), to proteins, affecting their biological activity (similar to phosphorylation). In normal physiology, transient activation of HBP/O-GlcNAc mechanisms is an adaptive, protective means to enhance cell survival; interventions that acutely suppress this pathway decrease tolerance to stress. Conversely, chronic dysregulation of HBP/O-GlcNAc mechanisms has been shown to be detrimental in certain pathological settings, including diabetes and cancer. Most of our understanding of the impact of sustained maladaptive HBP and O-GlcNAc protein modifications has been derived from adipose tissue, skeletal muscle and other non-cardiac tissues, as a contributing mechanism to insulin resistance and progression of diabetic complications. However, the long-term consequences of persistent activation of cardiac HBP and O-GlcNAc are not well-understood; therefore, the goal of this timely review is to highlight current understanding of the role of the HBP pathway in development of diabetic cardiomyopathy. © 2016 

Cardiac remodeling; Diabetic cardiomyopathy; Diastolic function; Hyperglycemia; O-GlcNAcylation; 1,2 dideoxy 2' propyl alpha dextro glucopyranose[2,1 dextro]delta2' thiazoline; 6 diazo 5 oxonorleucine; adrenergic receptor; alloxan; amino n phenyl carbamate; aminotransferase; azaserine; benzyl 2 acetamido 2 deoxy alpha dextro galactopyranoside; calcium calmodulin dependent protein kinase II; calcium ion; enzyme inhibitor; fructose 6 phosphate; glcnacstatin; glucosamine; glutamine fructose 6 phosphate aminotransferase; hexosamine; n acetylglucosamine; quinolinone 6 sulfonamide; thiamet g; unclassified drug; uridine diphosphate n acetylglucosamine; hexosamine; Article; calcium current; carbohydrate synthesis; cardiac muscle cell; diabetic cardiomyopathy; drug mechanism; enzyme activation; enzyme activity; enzyme inhibition; heart hypertrophy; heart left ventricle failure; heart muscle fibrosis; heart protection; human; molecular interaction; molecular pathology; mouse model; nonhuman; o glcnacylation; oxidative stress; protein analysis; protein expression; protein modification; protein phosphorylation; signal transduction; transcription regulation; transgenic mouse; upregulation; animal; biosynthesis; diabetes mellitus; diabetic cardiomyopathy; diabetic complication; glycosylation; heart; metabolism; pathology; pathophysiology; Animals; Diabetes Complications; Diabetes Mellitus; Diabetic Cardiomyopathies; Glycosylation; Heart; Hexosamines; Humans