Protein O-GlcNAcylation in Cardiac Pathologies: Past, Present, Future

Abstract

O-GlcNAcylation is a ubiquitous and reversible post-translational protein modification that has recently gained renewed interest due to the rapid development of analytical tools and new molecules designed to specifically increase the level of protein O-GlcNAcylation. The level of O-GlcNAc modification appears to have either deleterious or beneficial effects, depending on the context (exposure time, pathophysiological context). While high O-GlcNAcylation levels are mostly reported in chronic diseases, the increase in O-GlcNAc level in acute stresses such as during ischemia reperfusion or hemorrhagic shock is reported to be beneficial in vitro, ex vivo, or in vivo. In this context, an increase in O-GlcNAc levels could be a potential new cardioprotective therapy, but the ambivalent effects of protein O-GlcNAcylation augmentation remains as a key problem to be solved prior to their transfer to the clinic. The emergence of new analytical tools has opened new avenues to decipher the mechanisms underlying the beneficial effects associated with an O-GlcNAc level increase. A better understanding of the exact roles of O-GlcNAc on protein function, targeting or stability will help to develop more targeted approaches. The aim of this review is to discuss the mechanisms and potential beneficial impact of O-GlcNAc modulation, and its potential as a new clinical target in cardiology.

MicroRNAs in Cardiac Diseases

“…Increased global levels of protein O -GlcNAcylation has been shown to improve cardiac response after acute stress such as ischemia-reperfusion, MI and oxidative stress. [105]. Two other miRNAs belonging to the Dlk1 - Dio3 region are miR-410 and miR-495.…”

O-GlcNAc stimulation: A new metabolic approach to treat septic shock

“…: glucosamine, PUGNAc, NButGT) the level of protein O -GlcNAcylation. Whilst protein O -GlcNAcylation modulation seems to cause different effects in acute and chronic pathologies 7 , there is little evidence to suggest that a global increase in this post-translational modification could become a future therapeutic avenue to treat septic shock. In trauma-haemorrhage situations, glucosamine or PUGNAc administered during reperfusion increase survival of animals through an improvement in inflammatory responses and organ function 8 .…”

Molecular Basis of Cardiac and Vascular Injuries Associated With COVID-19

“…In humaninduced pluripotent stem cell-derived multipotent cardiac progenitor cells, knockdown of SON reduced proliferation and differentiation of cardiomyocytes, while increasing fibroblasts (40). OGT is an O-GlcNAc transferase that catalyzes the addition of the O-GlcNAc post-translational modification to proteins, which is essential in regulating the stress response, differentiation, nutrient sensing, and autophagy (41). O-GlcNAc level is increased during ischemia-reperfusion or hemorrhagic shock with a cardioprotective effect making augmentation of O-GlcNAc levels a potential new therapeutic option for cardiovascular dysfunction or ischemia/reperfusion (42).…”

“…OGT is an O-GlcNAc transferase that catalyzes the addition of the O-GlcNAc post-translational modification to proteins, which is essential in regulating the stress response, differentiation, nutrient sensing, and autophagy ( 41 ). O-GlcNAc level is increased during ischemia-reperfusion or hemorrhagic shock with a cardioprotective effect making augmentation of O-GlcNAc levels a potential new therapeutic option for cardiovascular dysfunction or ischemia/reperfusion ( 42 ). RORA is a nuclear receptor retinoic acid-related orphan receptor-α that has been recently identified in the heart to inhibit ANG II-induced pathological hypertrophy and cardiomyocyte death, repress IL-6 transcription, and its level is reduced in failing mouse and human hearts ( 43 ).…”