Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 297, Issue 5, Pages H1711-H1719Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00553.2009
Keywords
O-linked beta-N-acetylglucosamine; endoplasmic reticulum
Funding
- National Heart, Lung, and Blood Institute [R01-HL-083320, R01-HL-094419]
- American Heart Association National Center [0535270N]
- Kentucky Science and Engineering Foundation [KSEF-1667-RDE-011]
- American Heart Association Scientist Development [0835456N]
- National Institutes of Health Diabetes and Obesity Center [P20-RR-024489]
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Ngoh GA, Hamid T, Prabhu SD, Jones SP. O-GlcNAc signaling attenuates ER stress-induced cardiomyocyte death. Am J Physiol Heart Circ Physiol 297: H1711-H1719, 2009. First published September 4, 2009; doi:10.1152/ajpheart.00553.2009.-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.
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