The role of protein O-linked β- N-acetylglucosamine in mediating cardiac stress responses

• Published in: Biochimica et biophysica acta Vol. 1800; no. 2; pp. 57 - 66
• Main Authors: Chatham, John C., Marchase, Richard B.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2010
• Subjects: Acetylglucosamine - physiology; Animals; Calcium - metabolism; Calcium Channels - physiology; Capacitative calcium entry (CCE); Cardiotonic Agents - metabolism; Glucose - metabolism; Glutamine - metabolism; Hexosamine biosynthesis; Hexosamines - biosynthesis; Homeostasis - physiology; Humans; In Vitro Techniques; Membrane Proteins - physiology; Myocardial Reperfusion Injury - physiopathology; Myocytes, Cardiac - metabolism; Neoplasm Proteins - physiology; O-GlcNAc transferase; Orai1; ORAI1 Protein; Protein O-glycosylation; Protein Processing, Post-Translational; Proteins - metabolism; STIM1; Stress, Physiological - physiology; Stromal Interaction Molecule 1; Protein O-glycosylation; Orai1; O-GlcNAc transferase; STIM1; Hexosamine biosynthesis; Capacitative calcium entry (CCE)
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2009.07.004

The modification of serine and threonine residues of nuclear and cytoplasmic proteins by O-linked β- N-acetylglucosamine ( O-GlcNAc) has emerged as a highly dynamic post-translational modification that plays a critical role in regulating numerous biological processes. Much of our understanding of the mechanisms underlying the role of O-GlcNAc on cellular function has been in the context of its adverse effects in mediating a range of chronic disease processes, including diabetes, cancer and neurodegenerative diseases. However, at the cellular level it has been shown that O-GlcNAc levels are increased in response to stress; augmentation of this response improved cell survival while attenuation decreased cell viability. Thus, it has become apparent that strategies that augment O-GlcNAc levels are pro-survival, whereas those that reduce O-GlcNAc levels decrease cell survival. There is a long history demonstrating the effectiveness of acute glucose–insulin–potassium (GIK) treatment and to a lesser extent glutamine in protecting against a range of stresses, including myocardial ischemia. A common feature of these approaches for metabolic cardioprotection is that they both have the potential to stimulate O-GlcNAc synthesis. Consequently, here we examine the links between metabolic cardioprotection with the ischemic cardioprotection associated with acute increases in O-GlcNAc levels. Some of the protective mechanisms associated with activation of O-GlcNAcylation appear to be transcriptionally mediated; however, there is also strong evidence to suggest that transcriptionally independent mechanisms also play a critical role. In this context we discuss the potential link between O-GlcNAcylation and cardiomyocyte calcium homeostasis including the role of non-voltage gated, capacitative calcium entry as a potential mechanism contributing to this protection.