title: O-GlcNAc and the cardiovascular system.
abstract: The cardiovascular system is capable of robust changes in response to physiologic and pathologic stimuli through intricate signaling mechanisms. The area of metabolism has witnessed a veritable renaissance in the cardiovascular system. In particular, the post-translational β-O-linkage of N-acetylglucosamine (O-GlcNAc) to cellular proteins represents one such signaling pathway that has been implicated in the pathophysiology of cardiovascular disease. This highly dynamic protein modification may induce functional changes in proteins and regulate key cellular processes including translation, transcription, and cell death. In addition, its potential interplay with phosphorylation provides an additional layer of complexity to post-translational regulation. The hexosamine biosynthetic pathway generally requires glucose to form the nucleotide sugar, UDP-GlcNAc. Accordingly, O-GlcNAcylation may be altered in response to nutrient availability and cellular stress. Recent literature supports O-GlcNAcylation as an autoprotective response in models of acute stress (hypoxia, ischemia, oxidative stress). Models of sustained stress, such as pressure overload hypertrophy, and infarct-induced heart failure, may also require protein O-GlcNAcylation as a partial compensatory mechanism. Yet, in models of Type II diabetes, O-GlcNAcylation has been implicated in the subsequent development of vascular, and even cardiac, dysfunction. This review will address this apparent paradox and discuss the potential mechanisms of O-GlcNAc-mediated cardioprotection and cardiovascular dysfunction. This discussion will also address potential targets for pharmacologic interventions and the unique considerations related to such targets.
authors.affiliation: Institute of Molecular Cardiology, Diabetes and Obesity Center, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Physiology and Biophysics, University of Louisville, Louisville, KY, USA.
authors.forename: Sujith
authors.initials: S
authors.lastname: Dassanayaka
authors.affiliation: Institute of Molecular Cardiology, Diabetes and Obesity Center, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Physiology and Biophysics, University of Louisville, Louisville, KY, USA. Electronic address: Steven.P.Jones@Louisville.edu.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Jones
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D002319:Cardiovascular System / Q000378:metabolism*; D015444:Exercise; D006595:Hexosamines / Q000378:metabolism; D006801:Humans; D011499:Protein Processing, Post-Translational
chemical_list: D006595:Hexosamines; D000117:Acetylglucosamine
keywords: Heart failure; Hexosamine biosynthetic pathway; Hypertrophy; Ischemia–reperfusion injury; Mitochondria