Regulation of cardiac O-GlcNAcylation: More than just nutrient availability

Abstract

The post-translational modification of serine and threonine residues of nuclear, cytosolic, and mitochondrial proteins by O-linked β-N-acetyl glucosamine (O-GlcNAc) has long been seen as an important regulatory mechanism in the cardiovascular system. O-GlcNAcylation of cardiac proteins has been shown to contribute to the regulation of transcription, metabolism, mitochondrial function, protein quality control and turnover, autophagy, and calcium handling. In the heart, acute increases in O-GlcNAc have been associated with cardioprotection, such as those observed during ischemia/reperfusion. Conversely, chronic increases in O-GlcNAc, often associated with diabetes and nutrient excess, have been shown to contribute to cardiac dysfunction. Traditionally, many studies have linked changes in O-GlcNAc with nutrient availability and as such O-GlcNAcylation is often seen as a nutrient driven process. However, emerging evidence suggests that O-GlcNAcylation may also be regulated by non-nutrient dependent mechanisms, such as transcriptional and post-translational regulation. Therefore, the goals of this review are to provide an overview of the impact of O-GlcNAcylation in the cardiovascular system, how this is regulated and to discuss the emergence of regulatory mechanisms other than nutrient availability.

Keywords: Cardiomyocyte; GFAT; Heart; Metabolism; Nutrient regulation; O-GlcNAc; O-GlcNAc transferase (OGT); O-GlcNAcase (OGA).

Figure 1:

Illustration of the wide range of factors that result in increases or decreases in O-GlcNAc levels in cardiomyocytes or the heart, which are discussed in more detail in the text.

Figure 2:. Regulation of protein O-GlcNAc homeostasis:

Black line indicates changes in protein O-GlcNAc levels over an arbitrary period of time. In healthy cardiomyocytes, overall cellular O-GlcNAc levels vary within an optimal range over time periods of minutes, hours, or longer in response to different physiological stimuli due to changes in nutrient availability, regulation of GFAT, OGT, and OGA activities or alterations in the levels of these proteins. External stressors can lead to changes in O-GlcNAc levels beyond the optimal zone, either too high or too low, which can result in cellular dysfunction and potentially cell death depending on the duration of these excursions; however, brief pharmacologically induced increases in O-GlcNAc levels may be cardioprotective in the setting of ischemia/reperfusion or oxidative stress. This schematic illustrates overall changes in cellular O-GlcNAc levels and does not reflect the fact that O-GlcNAc levels can exhibit differential changes on individual proteins in response to both physiological and pathological stimuli; it also does not include the time of day dependent changes in O-GlcNAc that also occur in the heart.

Figure 3:. Illustration of the complex interactions associated with the regulation by and of protein O-GlcNAcylation:

Solid lines indicate established interactions, although not necessarily fully confirmed in the heart. Dotted lines indicate possible interactions that have yet to be established. There are no assumptions as to whether the interactions shown are positive or negative as this will likely be dependent on the specific stimulus and conditions (i.e., physiological or pathological). This is not a comprehensive illustration of all known interactions, but rather is focused on interactions discussed in the text with an emphasis on regulatory crosstalk known to be associated with O-GlcNAcylation or its regulatory enzymes (i.e. OGT, OGA, and GFAT). For example, both AMPK and CaMKII are known to regulate both OGT and GFAT and both are regulated by OGT; moreover, AMPK directly regulates glucose and fatty acid metabolism, which in turn influences HBP flux. In addition, AMPK contributes to transcriptional regulation of metabolism via its action on FoxO and PGC-1α, which in turn are both targets for O-GlcNAcylation. All relevant citations and abbreviations are included in the main body of the manuscript. OGT/OGA represents the O-GlcNAc cycle and the interactions shown could be influenced by either one or both of proteins. Note: Blue = metabolites/metabolic pathways; Purple = transcription factors; Green = all other proteins.