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Review
. 2014 Apr;142(1):62-71.
doi: 10.1016/j.pharmthera.2013.11.005. Epub 2013 Nov 25.

O-GlcNAc and the cardiovascular system

Sujith Dassanayaka  1 , Steven P Jones  2
Affiliations
Review

O-GlcNAc and the cardiovascular system

Sujith Dassanayaka et al. Pharmacol Ther. 2014 Apr.

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.

Keywords: Heart failure; Hexosamine biosynthetic pathway; Hypertrophy; Ischemia–reperfusion injury; Mitochondria.

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Conflict of interest statement

Conflict of Interest Statement

The authors have nothing to disclose.

Figures

Figure 1
Figure 1
Depiction of glucose entry into a cell and, subsequently, the hexosamine biosynthetic pathway (HBP). The four reactions and enzymes of the HBP are indicated along with corresponding inhibitors (red). The formation of UDP-GlcNAc, the donor for the O-GlcNAc modification, is the final product of the HBP. O-GlcNAc can be added to protein substrates via OGT. Conversely, OGA functions to remove this moiety. Inhibitors are highlighted in red and juxtaposed with their targets.
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