title: The role of protein O-linked beta-N-acetylglucosamine in mediating cardiac stress responses.
abstract: The modification of serine and threonine residues of nuclear and cytoplasmic proteins by O-linked beta-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.
authors.affiliation: Department of Medicine, Division of Cardiovascular Disease, Center for Free Radical Biology, Center for Aging and Clinical Nutrition Research Center, University of Alabama at Birmingham, Birmingham, AL, USA. jchatham@uab.edu
authors.forename: John C
authors.initials: JC
authors.lastname: Chatham
authors.forename: Richard B
authors.initials: RB
authors.lastname: Marchase
mesh_terms: D000117:Acetylglucosamine / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D002316:Cardiotonic Agents / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006595:Hexosamines / Q000096:biosynthesis; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D009363:Neoplasm Proteins / Q000502:physiology; D000071740:ORAI1 Protein; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology*; D000071737:Stromal Interaction Molecule 1
chemical_list: D015220:Calcium Channels; D002316:Cardiotonic Agents; D006595:Hexosamines; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D011506:Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D005973:Glutamine; D005947:Glucose; D002118:Calcium; D000117:Acetylglucosamine