O-GlcNAc signaling attenuates ER stress-induced cardiomyocyte death.
We previously demonstrated that the O-linked beta-N-acetylglucosamine (O-GlcNAc) posttranslational modification confers cardioprotection at least partially through mitochondrial-dependent mechanisms, but it remained unclear if O-GlcNAc signaling interfered with other mechanisms of cell death. Because ischemia/hypoxia causes endoplasmic reticulum (ER) stress, we ascertained whether O-GlcNAc signaling could attenuate ER stress-induced cell death per se. Before induction of ER stress (with tunicamycin or brefeldin A), we adenovirally overexpressed O-GlcNAc transferase (AdOGT) or pharmacologically inhibited O-GlcNAcase [via O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino-N-phenylcarbamate] to augment O-GlcNAc levels or adenovirally overexpressed O-GlcNAcase to reduce O-GlcNAc levels. AdOGT significantly (P < 0.05) attenuated the activation of the maladaptive arm of the unfolded protein response [according to C/EBP homologous protein (CHOP) activation] and cardiomyocyte death (reflected by percent propidium iodide positivity). Moreover, pharmacological inhibition of O-GlcNAcase significantly (P < 0.05) mitigated ER stress-induced CHOP activation and cardiac myocyte death. Interestingly, overexpression of GCA did not alter ER stress markers but exacerbated brefeldin A-induced cardiomyocyte death. We conclude that enhanced O-GlcNAc signaling represents a partially proadaptive response to reduce ER stress-induced cell death. These results provide new insights into a possible interaction between O-GlcNAc signaling and ER stress and may partially explain a mechanism of O-GlcNAc-mediated cardioprotection.
Ngoh
Gladys A
GA
Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky, USA.
Hamid
Tariq
T
Prabhu
Sumanth D
SD
Jones
Steven P
SP
D000117:Acetylglucosamine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D000222:Adaptation, Physiological; D000818:Animals; D000831:Animals, Newborn; D020126:Brefeldin A / Q000494:pharmacology; D016923:Cell Death; D015687:Cell Hypoxia; D002478:Cells, Cultured; D019610:Cytoprotection; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology; D048448:Phenylcarbamates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000378:metabolism; D014162:Transfection; D014415:Tunicamycin / Q000494:pharmacology; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
C497251:Ddit3 protein, rat; D004791:Enzyme Inhibitors; D010091:Oximes; D048448:Phenylcarbamates; D014415:Tunicamycin; C068836:N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime; D051742:Transcription Factor CHOP; D020126:Brefeldin A; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine