Cardioprotection by N -Acetylglucosamine Linkage to Cellular Proteins

Abstract

Background-The modification of proteins with O-linked ␤-N-acetylglucosamine (O-GlcNAc

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

“…Recent data suggests that O-GlcNAc is one component of the cellular stress response that is relevant to a variety of models of injury in several cell and tissue types. OGlcNAc levels become elevated in response to numerous forms of cell stress and tissue injury including: heat stress (Sohn et al 2004;Zachara et al 2004b), oxidative stress Zachara et al 2004b), ethanolic stress (Zachara et al 2004b;Ngoh et al 2009b), genotoxic stress (doxorubicin, belocin, and UVB irradiation; Zachara et al 2004bZachara et al , 2011aLove et al 2010), reductive stress (iodoacetamide; Zachara et al 2004b), ER stress (dithiothreitol and tunicamycin; Zachara et al 2004b;Ngoh et al 2009b), hypoxia reoxygenation (Ngoh et al 2009a;Ngoh et al 2008;Ngoh et al 2011), osmotic stress (NaCl, sorbitol, and sucrose; Zachara et al 2004b;Zou et al 2007), ATP depletion (sodium arsenite; Zachara et al 2004b), ischemia reperfusion injury (Champattanachai et al 2007(Champattanachai et al , 2008Fulop et al 2007a, b;Hwang et al 2010;Jones et al 2008;Laczy et al 2010;Liu et al 2006Liu et al , 2007Nagy et al 2006;Ngoh et al 2008Ngoh et al , 2009aNgoh et al , b, 2011Pang et al 2002;Zou et al 2009), and trauma hemorrhage Yang et al 2006a;Zou et al 2007Zou et al , 2009). This response occurs in primary and transformed cells, as well as in tissues in vivo and ex vivo.…”

“…For example, O-GlcNAc appears to regulate many of the hallmarks of I/R injury such as calcium overload, oxidative damage, ER stress, and mitochondrial aberrations . Elevating OGlcNAc levels with glucosamine, PUGNAc (O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate), or thiamet G (TMG, 2-ethylamino-3aR, 6S, 7R, 7aR-tetrahydro-5R-hydroxymethyl-5H-pyrano[3, 2-d]thiazole-6, 7-diol) leads to improved function and reduced tissue death in both ex vivo and in vivo models of I/R injury in the heart (Liu et al 2007;Liu et al 2006;Fulop et al 2007b;Jones et al 2008). Collectively, these data suggest that the stress-induced elevation of the O-GlcNAc modification is a pro-survival response of cells and tissues (Champattanachai et al 2007(Champattanachai et al , 2008Hwang et al 2010).…”

“…2), and is responsible for nonspecifically allowing small molecules (<1.5 kDa) to enter and exit the mitochondrial matrix (Crow et al 2004). One postulated mechanism for the cytoprotective nature of O-GlcNAc is through the regulation of mitochondrial function Jones et al 2008) by reducing calcium overload, dampening ROS production, and preventing mPTP formation (Ngoh et al , 2011Jones et al 2008). It has been suggested that O-GlcNAc may regulate the mPTP directly by modifying and modulating the voltage-dependent anion channel (VDAC; Ngoh et al 2008;Jones et al 2008; Fig.…”

“…2). For example, deletion of OGT led to reduced OGlcNAcylation of VDAC, sensitizing cells to mitochondrial membrane potential collapse and mPTP formation Jones et al 2008). Notably, formation of the mPTP is also promoted by active GSK3β (Juhaszova et al 2004;Miura and Miki 2009), which is inhibited in some models by stress-induced O-GlcNAcylation (Kazemi et al 2010;Ku et al 2010).…”

Cardioprotective Pathways During Reperfusion: Focus on Redox Signaling and Other Modalities of Cell Signaling

“…Some evidence indicates a potential mitochondrial isoform of OGT (93,128,130,131). Moreover, it has been reported that augmentation of O-GlcNAcylation levels in cardiomyocytes attenuates H 2 O 2 -induced loss of mitochondrial membrane potential (23,93,128,131) and that this may be due to O-GlcNAcylation of mitochondrial proteins such as VDAC. All these studies suggest that ROS from mitochondria contribute to the regulation of O-GlcNAcylation of proteins, which could, in turn, modulate the mitochondria response to oxidative-stress.…”