Associate editor: R.A. Prough
O-GlcNAc and the cardiovascular system

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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.

Introduction

Glucose not only functions as a ubiquitous source of energy but also confers significant capacity for inter/intracellular signaling. Upon entering a cell, glucose is phosphorylated to glucose-6-phosphate. During glycolysis it is further metabolized to fructose-6-phosphate permitting entry into a host of accessory pathways of glucose metabolism; one such pathway is the hexosamine biosynthetic pathway (HBP). The HBP culminates in the formation of a high-energy glycoside precursor (UDP-GlcNAc) for the posttranslational modification of nuclear and cytoplasmic proteins. This resulting β-O-linkage of N-acetylglucosamine (O-GlcNAc) to proteins has been identified in altering expression, translation, and function of the target proteins. Recently O-GlcNAc has emerged as key player in the primary pathophysiology of many cardiovascular diseases. This review focuses on the role of O-GlcNAc in the cardiovascular system and examines the therapeutic potential for pharmacological management of this signaling mechanism.

Section snippets

Hexosamine biosynthetic pathway

Approximately 5% of intracellular glucose enters the HBP. The four enzymatic reactions of the HBP convert fructose-6-phosphate to uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc), the monosaccharide donor for the O-GlcNAc modification. The first reaction is the rate-limiting conversion of fructose-6-phosphate to glucosamine-6-phosphate by l-glutamine: fructose-6-phosphate amidotransferase (GFAT) with the concomitant conversion of Gln to Glu (Marshall, Bacote and Traxinger, 1991, Broschat et

GFAT

Flux through the HBP can be altered based on the availability of nutrients and activity of enzymes. The availability of glucose to shunt through the HBP is paramount. Further progression through the HBP requires sources of glutamine, glucosamine and acetyl-CoA. The first and rate-limiting enzyme of the HBP is GFAT (Marshall, Bacote & Traxinger, 1991), which is highly conserved and exists in two different isoforms, GFAT1 and GFAT2 (Oki et al., 1999). GFAT1 is expressed in the pancreas, placenta,

O-GlcNAcylation and phosphorylation

Because it shares some similarities with phosphorylation, O-GlcNAcylation, and its impact on signaling, can become exceptionally complicated. Both O-GlcNAcylation and phosphorylation modifications occur on serine and threonine residues, are dynamically added and removed, and alter function of proteins (Hart et al., 1996). Although hundreds of genes regulate phosphorylation, only two known genes encode enzymes for the addition and removal of O-GlcNAc in mammals. Interestingly, a gene with

O-GlcNAc acts as an alarm or stress signal

The O-GlcNAc post-translational modification may sense and trigger a pro-adaptive response to cellular stressors. Some of the earliest evidence to support such a contention involved the association between hyperglycemia and O-GlcNAcylation and/or OGT (Akimoto et al., 2000, Konrad et al., 2000, Liu et al., 2000, Akimoto et al., 2001). Although this can be retrospectively viewed as ‘stress’ studies, the first bona fide investigation of O-GlcNAc as a stress signal came in 2004 (Zachara et al., 2004

Acute cardioprotection

The O-GlcNAc modification confers protection to subsequent lethal insults, which has been reviewed extensively (Hart et al., 1996, Jones, 2005, Chatham et al., 2008, Ngoh and Jones, 2008, Laczy et al., 2009, Ngoh et al., 2010, Lima et al., 2012, Zachara, 2012, Bond and Hanover, 2013), elsewhere. Briefly, in response to myocardial ischemia–reperfusion injury – which is characterized by calcium overload, oxidative stress, and ER stress – global levels of O-GlcNAcylation are augmented (Liu et al.,

O-GlcNAc mediates diabetic cardiac dysfunction?

Similar to the basic cell studies tying O-GlcNAc to diabetic pathogenesis, several groups have suggested an association between increased O-GlcNAcylation and cardiac dysfunction. At a reductionist level, cells grown in hyperglycemic conditions demonstrated reduced ATP production as a potential result of altered mitochondrial proteins (Hu et al., 2005). Increased O-GlcNAcylation, secondary to hyperglycemia, may lead to depressed function of mitochondrial electron transport complexes I, III, and

O-GlcNAc modulates vascular activity

Sustained alteration of cardiovascular reactivity can result in hypertension, a primary risk factor for cardiovascular disease. Deranged vascular activity, endothelial reactivity, and hypersensitivity to vasoconstrictors are all hallmarks of hypertension and vascular dysfunction. Interestingly, the development of these hallmark characteristics appears to coincide with augmented O-GlcNAcylation. Lima et al. described increased O-GlcNAcylation in the vasculature of hypertensive rats (Lima et al.,

Exercise

Because O-GlcNAc is a fuel or metabolic sensor, several groups have interrogated the potential role of O-GlcNAcylation in exercise. Recently, Bennet et al. studied the effects of exercise on O-GlcNAcylation in diabetic mice (Bennett et al., 2013). They found that exercise treatment of diabetic mice resulted in improved rate of relaxation (Tau) and a reduction in O-GlcNAcylation. Also, Belke showed decreased protein O-GlcNAcylation and expression of OGT in mice with exercise-induced (i.e.

Conclusion

O-GlcNAcylation plays a vital role in cardiac and vascular function, especially during disease. Although O-GlcNAcylation uniformly promotes cardiomyocyte survival in the context of acute cell injury, the role of O-GlcNAc in the vasculature or in the chronically failing/diabetic heart is less clear-cut. So, is any of this clinically relevant? In the case of acute cardioprotection, therapeutic augmentation of O-GlcNAc levels is a clinically feasible option. One such strategy would be to limit

Funding sources

The Jones Laboratory is supported by National Institutes of Health grants (R01 HL083320, R01 HL094419, P20 GM103492, and P01 HL078825).

Conflict of interest statement

The authors have nothing to disclose.

Acknowledgments

The authors acknowledge the work of previous trainees and staff in the laboratory, and, all of the other laboratories that have made meaningful contributions to the field. Unfortunately, space concerns required that not all relevant works could be cited.

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