View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Kanazawa University Repository for Academic Resources Enzymatic and non-enzymatic post-translational modifications linking diabetes and heart disease 著者 Yamamoto Yasuhiko, Yamamoto Hiroshi journal or Journal of Diabetes Investigation publication title volume 6 number 1 page range 16-17 year 2015-01-01 URL http://hdl.handle.net/2297/45821 doi: 10.1111/jdi.12248 COMMENTARY Enzymatic and non-enzymatic post-translational modifications linking diabetes and heart disease Diabetes-related morbidity and mortality has received considerable attention as a however, its flux is upregulated in dia- is evident in the increased prevalence of key factor in diabetic cardiac pathology2,3. betic cardiomyocytes4. The rate-limiting cardiovascular diseases and the high-risk In contrast to non-enzymatic glycation enzyme glutamine, fructose-6-phosphate of heart failure. Diabetic cardiomyopathy reactions, O-GlcNAc glycosylation is a aminotransferase (GFAT), converts fruc- is a well-known complication of diabetes, reversible and labile post-translational tose-6-phosphate to glucosamine-6-phos- and is defined as a ventricular dysfunc- modification. phate, which is then converted into tion independent of coronary heart After entering a cell, glucose is phos- UDP-GlcNAc and transferred onto target diseases and hypertension. The Framing- phorylated to glucose-6-phosphate (Fig- proteins by O-GlcNAc transferase ham study firmly established an epidemi- ure 1). It is further metabolized during (OGT). The enzyme, O-GlcNAcase, cata- ological link between diabetes and heart glycolysis to fructose-6-phosphate, which lyzes the removal of the O-GlcNAc failure1.Diabetescausesmetabolicdistur- leads to accessory pathways of glucose adduct from O-GlcNAcylated proteins bances, cardiac fibrosis, endothelial and metabolism; one such pathway is the (Figure 1)2. O-GlcNAcylation is reported vascular smooth muscle cell dysfunctions, hexosamine biosynthesis pathway. Under to be involved in a number of cellular altered contractile performance, and normal physiological conditions, approxi- processes including signal transduction, arrhythmia. The underlying mechanisms mately 5% of intracellular glucose enters protein–protein interactions, translation, of the adverse effects of diabetes on the the hexosamine biosynthesis pathway; protein degradation and gene expression heart remain poorly understood. How- ever, it is certain that diabetic heart dis- ease is a consequence of multiple factors including uncontrolled hyperglycemia, D-glucose insulin resistance and dyslipidemia. Hexokinase Chronic hyperglycemia causes glucose Glucose-6-phosphate Methyglyoxal Methylglyoxal Glycation Glucose-6-phoshate synthase toxicity, which mediates the detrimental isomerase effects of diabetes through the activation Fructose-6-phoshate Hexosamine of a number of pathways, such as the biosynthesis pathway polyol pathway, oxidative stress, mito- Glyceraldehyde-3-phoshate GFAT chondrial dysfunction, activation of pro- GAPDH tein kinases, hexosamine biosynthesis 1,3-bisphosphoglycerate pathway and non-enzymatic glycation Glucosamine kinase/Hexokinase Glucosamine-6-phosphate Glucosamine reaction. The hexosamine biosynthesis Pyruvate pathway generates uridine diphosphate- Glucosamine-6-phosphate acetyltransferase N-acetylglucosamine (UDP-GlcNAc), Glycolysis N-acetylglucosamine kinase N-acetylglucosamine-6-phoshate N-acetylglucosamine which is an activated precursor for both N-acetylglucosamine N-linked and O-linked glycosylation of phosphomutase proteins, and the substrate for b-O-linked N-acetyglucosamine-1-phosphate fi UDP-N-acetylglucosamine GlcNAc (O-GlcNAc) modi cation of pro- pyrophosphorylase teins (Figure 1). Recently, O-GlcNAc Glycosylation UDP-GlcNAc GlcNAcylated protein covalent modification of cardiac proteins Glycolipid synthesis OGT O-GlcNAcase GPI-anchored protein synthesis Unmodified protein *Corresponding author. Yasuhiko Yamamoto Tel.: +81-76-265-2181 Figure 1 | Hexosamine biosynthesis pathway. GAPDH, glyceraldehyde 3-phosphate Fax: +81-76-234-4217 dehydrogenase; GFAT, glutamine:fructose-6-phosphate amidotransferase; OGT, O-linked E-mail address: [email protected] N-acetylglucosamine (GlcNAc) transferase; O-GlcNAcase, O-GlcNAc-selective Received 1 May 2014; revised 2 May 2014; accepted N N 8 May 2014 beta- -acetylglucosaminidase; UDP-GlcNAc, uridine diphosphate- -acetylglucosamine. 16 JDiabetesInvestVol.6No.1January2015 ª 2014 The Authors. Journal of Diabetes Investigation published by Asian Association of the Study of Diabetes (AASD) and Wiley Publishing Asia Pty Ltd This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. COMMENTARY http://onlinelibrary.wiley.com/journal/jdi Commentary alteration4. Recently, O-GlcNAcylation diabetic rat myocardium, including the glycosylation. Nature 2013; 502: 372– has been shown in the regulation of car- sarcoplasmic reticulum Ca2+ adenosine 376. diomyocyte excitation-contraction cou- triphosphatase (ATPase; SERCA2) and 3. McLarty JL, Marsh SA, Chatham JC. plingbyinfluencing intracellular Ca2+ ryanodine receptor 2 (RYR2), a Ca2+ Post-translational protein modification homeostasis5. The multifunctional Ca2+ release channel6. Remodeling and degra- by O-linked N-acetyl-glucosamine: its and calmodulin-dependent protein dation of the extracellular matrix is also role in mediating the adverse effects kinase II (CaMKII) is a serine-threonine affected in diabetes as a result of reduced of diabetes on the heart. Life Sci 2013; kinase that is activated by an increase in expression of matrix metalloproteinases 92: 621–627. cellular Ca2+. The disruption of normal and consequent lower collagen turnover7. 4. Dassanayaka S, Jones SP. O-GlcNAc intracellular Ca2+ homeostasisisthe Binding of AGE to the receptor for AGE and the cardiovascular system. event mainly responsible for initiating (RAGE) on fibroblasts stimulates collagen Pharmacol Ther 2014; 142: 62–71. and perpetuating myocardial dysfunction, production, further compromising ven- 5. Nagy T, Champattanachai V, Marchase electrical instability, and arrhythmia. The tricular compliance8.Wealsoreported RB, et al. Glucosamine inhibits CaMKII regulates Ca2+ homeostasis pro- that AGE and RAGE impaired Ca2+ angiotensin II-induced cytoplasmic + teins in the myocardium. Recently, it has homeostasis in diabetic mouse myocytes; Ca2 elevation in neonatal been reported that O-GlcNAc modifica- thus, accounting for the abnormal con- cardiomyocytes via protein-associated tion of CaMKII leads to cardiac arrhyth- tractile and relaxation functions9. O-linked N-acetylglucosamine. Am J mias associated with diabetes, which are Diabetic cardiomyopathy involves vari- PhysiolCellPhysiol2006; 290: C57–C65. linked to heart failure and sudden car- ous complex functional and structural 6. Bidasee KR, Nallani K, Yu Y, et al. diac death2.CaMKIIfusionwithO-Glc- abnormalities. Recent findings highlight Chronic diabetes increases advanced NAc leads to chronic overactivation of the dynamic O-GlcNAcylation and irre- glycation end products on cardiac CaMKII, triggering arrhythmias, and versible glycation of fundamental cardio- ryanodine receptors/calcium-release inhibition of O-GlcNAcylation of CaM- myocyte proteins in the context of channels. Diabetes 2003; 52: 1825– KII prevented the occurrence of arrhyth- diabetes. This can potentially be used to 1836. mias2. In addition to direct O-GlcNAc study enzymatic and non-enzymatic 7. Van Linthout S, Seeland U, Riad A, modification of proteins involved in exci- post-translational modifications associated et al. Reduced MMP-2 activity tation-contraction coupling, nuclear with glucose metabolism for diabetic contributes to cardiac fibrosis in O-GlcNAcylation of transcription factors, cardiomyopathy interventions. experimental diabetic histones and ribonucleic acid (RNA) cardiomyopathy. Basic Res Cardiol polymerase II has been known to alter Yasuhiko Yamamoto*, Hiroshi 2008; 103: 319–327. gene transcription, resulting in cardiac Yamamoto 8. Yamazaki KG, Gonzalez E, Zambon AC. deterioration in patients with diabetes3. Department of Biochemistry and Crosstalk between the renin- Compared with the dynamic and Molecular Vascular Biology, Kanazawa angiotensin system and the advance enzymatic regulation of O-GlcNAcyla- University Graduate School of Medical glycation end product axis in the tion, non-enzymatic glycation-modifica- Sciences, Kanazawa, Japan heart: role of the cardiac fibroblast. J tion is generally irreversible and Cardiovasc Transl Res 2012; 5: 805–813. obstructive. 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