The O-GlcNAc dichotomy: when does adaptation become pathological?

Abstract

O-Linked attachment of β-N-acetylglucosamine (O-GlcNAc) on serine and threonine residues of nuclear, cytoplasmic, and mitochondrial proteins is a highly dynamic and ubiquitous post-translational modification that impacts the function, activity, subcellular localization, and stability of target proteins. Physiologically, acute O-GlcNAcylation serves primarily to modulate cellular signaling and transcription regulatory pathways in response to nutrients and stress. To date, thousands of proteins have been revealed to be O-GlcNAcylated and this number continues to grow as the technology for the detection of O-GlcNAc improves. The attachment of a single O-GlcNAc is catalyzed by the enzyme O-GlcNAc transferase (OGT), and their removal is catalyzed by O-GlcNAcase (OGA). O-GlcNAcylation is regulated by the metabolism of glucose via the hexosamine biosynthesis pathway, and the metabolic abnormalities associated with pathophysiological conditions are all associated with increased flux through this pathway and elevate O-GlcNAc levels. While chronic O-GlcNAcylation is well associated with cardiovascular dysfunction, only until recently, and with genetically modified animals, has O-GlcNAcylation as a contributing mechanism of cardiovascular disease emerged. This review will address and critically evaluate the current literature on the role of O-GlcNAcylation in vascular physiology, with a view that this pathway can offer novel targets for the treatment and prevention of cardiovascular diseases.

Keywords: O-GlcNAc; cardiovascular physiology; intracellular signaling.

Figure 1.. Depiction of the hexosamine biosynthesis and intracellular O-GlcNAcylation pathways, and how they deviate from classical glycolysis

While this pathway is presented in an endothelial cell, it is conserved among all cell types.

Figure 2.. The impact of acute and chronic O-GlcNAc levels on the physiological system under stress

While this pathway is presented in vascular smooth muscle cells, the acute vs. chronic effects of O-GlcNAcylation are observed in all cell types (both primary cells and cell lines). OSMI is an OGT inhibitor and KO OGT is knockdown of OGT gene. Created with BioRender.com.

Figure 3.. Chronic O-GlcNAcylation has been associated with a plethora of deleterious vascular phenotypes that can then contribute to the development and maintenance of cardiovascular disease

Reported dysfunctions include impairment of endothelial nitric oxide synthase (eNOS), vascular smooth muscle cell (VSMC) hyper-contractility, VSMC de-differentiation, calcification, and inflammation. Collectively, this means that O-GlcNAcylation has a critical point in which it shifts from an essential adaptation to stress to a contributing mechanism of disease. Created with BioRender.com.