The Role of O-GlcNAcylation for Protection against Ischemia-Reperfusion Injury

Abstract

Ischemia reperfusion injury (IR injury) associated with ischemic heart disease contributes significantly to morbidity and mortality. O-linked β-N-acetylglucosamine (O-GlcNAc) is a dynamic posttranslational modification that plays an important role in numerous biological processes, both in normal cell functions and disease. O-GlcNAc increases in response to stress. This increase mediates stress tolerance and cell survival, and is protective. Increasing O-GlcNAc is protective against IR injury. Experimental cellular and animal models, and also human studies, have demonstrated that protection against IR injury by ischemic preconditioning, and the more clinically applicable remote ischemic preconditioning, is associated with increases in O-GlcNAc levels. In this review we discuss how the principal mechanisms underlying tissue protection against IR injury and the associated immediate elevation of O-GlcNAc may involve attenuation of calcium overload, attenuation of mitochondrial permeability transition pore opening, reduction of endoplasmic reticulum stress, modification of inflammatory and heat shock responses, and interference with established cardioprotective pathways. O-GlcNAcylation seems to be an inherent adaptive cytoprotective response to IR injury that is activated by mechanical conditioning strategies.

Keywords: O-GlcNAc; cardioprotection; ischemia-reperfusion injury.

Figure 1

The hexosamine biosynthsis pathway (HBP) and protein O-GlcNAcylation. Enzymes are illustrated by orange circles. Blockers are written in red. Abbreviations: GFAT: l-glutamine-d-fructose 6-phosphate amidotransferase; UDP-GlcNAc: UDP-N-acetylglucosamine; OGT: uridine-diphospho-N-acetylglucosamine:polypeptide β-N-acetylglucosaminyltransferase; O-GlcNAcase: β-N-acetylglucosaminidase; DON: 6-diazo-5-oxo-norleucine; UDP-5SGlcNAc: uridine diphospho-5-thio-N-acetylglucosamine; TTO4: 2[(4-chlorophenyl)imino]tetrahydro-4-oxo-3-[2-tricyclo(3.3.1.13.7)dec-1-ylethel]; PUGNAc: O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate; NAG:1,2-Dideoxy-2′-methyl-α-d-glucopyranoso-[2,1-d]-δ2′-thiazoline; NButGT:1,2-dideoxy-2′-propyl-α-d-glucopyranoso-[2,1-d]-δ2′-thiazoline. GFAT can be inhibited by glutamine analogue azaserine (O-diazoacetyl-L-serine) or DON. OGT can be inhibited by the uridine analogue alloxan, substrate analog of O-GlcNAc UDP-5SGlcNAc, or with TTO4, whereas O-GlcNAcylation of proteins can be rapidly increased by inhibiting O-GlcNAcase with PUGNAc, Thiamet G, NAG, or NButGT. Alloxan has also shown to have an inhibitory effect on O-GlcNAcase.

Figure 2

(a,b) Recovery of contractile force in atrial trabeculae from non-diabetic (a) and diabetic (b) patients, perfused with control and RIC dialysate from non-diabetic and diabetic patients; (c,d) O-GlcNAc levels in atrial trabeculae from non-diabetic (c) and diabetic (d) patients, perfused with control and RIC dialysate from non-diabetic and diabetic patients; (e,f) OGT activity in atrial trabeculae from non-diabetic (e) and diabetic (f) patients, perfused with control and RIC dialysate from non-diabetic and diabetic patients; (g,h) O-GlcNAcase activity in atrial trabeculae from non-diabetic (g) and diabetic (h) patients, perfused with control and RIC dialysate from non-diabetic and diabetic patients. Data are mean ± SEM. Originally published Cardiovasc Res. 2013 Feb 1; 97(2): 369–378 [23]. Reproduced with permission.

Figure 3

Summary of potential mechanisms by which O-GlcNAc confers protection. The mechanisms involve attenuation of endoplasmic reticulum (ER) stress, interaction with established cardioprotective pathways, predominantly Akt, inhibition of mitochondrial permeability transition pore (MPTP), attenuation of calcium overload, reactive oxygen species (ROS), heat shock protein (HSP), and cytokine production that reduce systemic inflammatory response. Other abbreviations as in Figure 1.