Insights into the role of maladaptive hexosamine biosynthesis and O-GlcNAcylation in development of diabetic cardiac complications. (February 2017)

• Record Type: Journal Article
• Authors: Qin, Cheng Xue; Sleaby, Rochelle; Davidoff, Amy J.; Bell, James R.; De Blasio, Miles J.; Delbridge, Leanne M.; Chatham, John C.; Ritchie, Rebecca H.
• Is Part Of: Pharmacological research. Volume 116(2017:Feb.)
• Page Start: 45
• Page End: 56
• Publication Date: 2017-02
• Subjects: AGE Advanced glycation end product -- Azaserine O-diazoacetyl-l-serine -- BAG Benzyl-2-acetamido-2-deoxy-a-d-galactopyranoside -- cAMP Cyclic adenosine-3′5′-monophosphate -- CaMKII Ca2+/calmodulin-dependent protein kinase II -- CRAC Ca2+ release activated Ca2+ channel -- CTD C terminal domain -- DAG Diacylglycerol -- DON 6-diazo-5-oxonorleucine -- EC Excitation contraction -- GLUT-4 Glucose transporter-4 -- eNOS Endothelial nitric oxide synthase -- HBP Hexosamine biosynthesis pathway -- GFAT Glutamine fructose-6-phosphate amidotransferase -- HF Heart failure -- IP3 Inositol triphosphate -- IP3-1R Inositol triphosphate-1 receptor -- ISO Isoprenaline -- LV Left ventricle/ventricular -- MHC Myosin heavy chain -- MLC Myosin light chain -- mOGT Mitochondrial OGT -- NButGT 1, 2-dideoxy-2′-propyl-α-d-glucopyranoso-[2, 1-D]-Δ2′-thiazoline -- ncOGT Nucleocytoplasmic OGT -- NCX Na+/Ca2+ exchanger -- NOS Nitric oxide synthases -- NFAT Calcineurin-nuclear factor of activated T cell -- OGA O-GlcNAcase -- O-GlcNAc O-linked β-N-acetylglucosamine -- OGT O-GlcNAc transferase -- PE Phenylephrine -- PIP2 Phosphatidylinositol (4, 5)-biphosphate -- PIP3 Phosphatidylinositol (3, 4, 5)-triphosphate -- PKC Protein kinase C -- PLB Phospholamban -- PLC Phospholipase C -- PUGNAc O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino N-phenyl carbamate -- ROS Reactive oxygen species -- SERCA Sarcoplasmic reticulum Ca2+-ATPase -- 5S-GlcNAc 5-thioglucosamine -- SOD Superoxide dismutase -- Sp1 Specificity protein 1 -- STIM1 Stromal interaction molecule 1 -- STZ Streptozotocin -- T1DM Type 1 diabetes mellitus -- T2DM Type 2 diabetes mellitus -- Thiamet G O-(2-acetamido-2-deoxy-d-glucopyranoseylidene) -- TIMP Tissue inhibitor of metalloproteinases -- TT04 2H-1, 3-thiazine-6-carboxylic acid, 2-[(4-chlorophenyl) imino] tetrahydro-4-oxo-3-(2-tricyclo[3.3.1.13, 7] dec-1-ylethyl-) -- UDP-GlcNAc Uridine diphosphate-N-acetylglucosamine; O-GlcNAcylation -- Diabetic cardiomyopathy -- Hyperglycemia -- Diastolic function -- Cardiac remodeling; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2016.12.016
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: 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.