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.
Highlights
Stressors triggering organ damage and disease continuously influence the cells of biological organisms
We demonstrated that cardioprotection by Ischemic preconditioning (IPC) was associated with increased myocardial glucose uptake, which may contribute to the mechanism by which IPC increases O-GlcNAc levels [21]
To test the influence of O-GlcNAc in protection by the more clinically relevant Remote ischemic conditioning (RIC), we demonstrated that dialysate from healthy volunteers exposed to RIC improved post-ischemic recovery and increased myocardial O-GlcNAc levels in human isolated atrial trabeculae subjected to IR injury (Figure 2) [23]
Summary
Stressors triggering organ damage and disease continuously influence the cells of biological organisms. In neonatal rat cardiac myocytes, augmentation of O-GlcNAc levels by treatment with PUGNAc, glucosamine, OGT overexpression, or O-GlcNAcase inhibition with a NAG-thiazoline derivative significantly attenuated loss of mitochondrial membrane potential in a dose-dependent manner after exposure to H2O2, as assessed by fluorescent cationic dye, JC-1, or TMRE fluorescence [20,25]. Genetic overexpression of OGT, or inhibition of O-GlcNAcase, increased O-GlcNAc and protected neonatal rat cardiac myocytes from cell death following hypoxia–reoxygenation, and aggravated the loss of mitochondrial membrane potential assessed by changes in TMRE fluorescence. Following IR of isolated neonatal rat ventricular myocytes, increasing O-GlcNAc levels by glucosamine treatment, OGT overexpression, and O-GlcNAcase inhibition using a NAG-thiazoline derivative decreased cytochrome C release, reflecting attenuated mPTP opening [25]. The mechanisms are not fully understood, and it is not known whether a direct effect of increased intracellular O-GlcNAc content and O-GlcNAcylation of mPTP subunits, or an indirect effect through attenuation of calcium overload and ROS production prevails
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