Protein O‐GlcNAcylation in the heart

Abstract

O‐GlcNAcylation is a ubiquitous post‐translational modification that is extremely labile and plays a significant role in physiology, including the heart. Sustained activation of cardiac O‐GlcNAcylation is frequently associated with alterations in cellular metabolism, leading to detrimental effects on cardiovascular function. This is particularly true during conditions such as diabetes, hypertension, cardiac remodelling, heart failure and arrhythmogenesis. Paradoxically, transient elevation of cardiac protein O‐GlcNAcylation can also exert beneficial effects in the heart. There is compelling evidence to suggest that a complex interaction between O‐GlcNAcylation and phosphorylation also exists in the heart. Beyond direct functional consequences on cardiomyocytes, O‐GlcNAcylation also acts indirectly by altering the function of transcription factors that affect downstream signalling. This review focuses on the potential cardioprotective role of protein O‐GlcNAcylation during ischaemia‐reperfusion injury, the deleterious consequences of chronically elevated O‐GlcNAc levels, the interplay between O‐GlcNAcylation and phosphorylation in the cardiomyocytes and the effects of O‐GlcNAcylation on other major non‐myocyte cell types in the heart.

O-Linked β-N-Acetylglucosamine Modification: Linking Hypertension and the Immune System

“…Therefore, an overabundance of nutrients ( 18 ), as seen in diabetic or hyperlipidemic subjects, may overload the HBP flux, leading to increased protein O-GlcNAcylation ( 19 ). In addition to diabetes, increased O-GlcNAc levels have been reported in different experimental models of hypertension ( 6 , 20 , 21 ), cardiac hypertrophy ( 22 , 23 ), cardiac dysfunction ( 22 , 24 , 25 ), as well as in response to agonists such as angiotensin II (Ang II) ( 6 ) and endothelin-1 (ET-1) ( 9 , 10 ). The fact that O-GlcNAc impacts biological functions that are not totally linked to altered nutrient availability, raised the suggestion that other mechanisms regulating O-GlcNAcylation may participate in the pathophysiology of hypertension.…”

“…Excessive chronic O-GlcNAcylation has been shown both in humans and animal models of myocardial dysfunction, cardiac remodeling, aortic banding, and hypertension ( 22 , 25 – 27 ). Hyperglycemia in Zucker (diabetic fatty) rats leads to high O-GlcNAc levels along with attenuated cardiomyocytes calcium peak and prolonged time to relaxation and, consequently, to impaired cardiac contraction and relaxation in these animals ( 28 ).…”

“…Therefore, O-GlcNAcylation regulates local and systemic RAAS, which may contribute to the progression of hypertension. Finally, high levels of O-GlcNAcylation driven by high glucose or glucosamine treatment leads to impaired vascular endothelial and smooth muscle cells function in human and rat ( 11 , 25 , 44 – 46 ), a phenotype closely associated with hypertension ( 29 ). In this sense, there is direct evidence that elevated levels of protein O-GlcNAcylation in endothelial cells impairs endothelium-dependent relaxation ( 44 , 47 – 49 ), demonstrating that O-GlcNAcylation leads to endothelial dysfunction.…”

“…In this sense, there is direct evidence that elevated levels of protein O-GlcNAcylation in endothelial cells impairs endothelium-dependent relaxation ( 44 , 47 – 49 ), demonstrating that O-GlcNAcylation leads to endothelial dysfunction. Furthermore, O-GlcNAcylation of vascular smooth muscle cells augments vascular response to contractile agonists ( 50 , 51 ) and favors vascular calcification ( 52 – 54 ), resulting in high blood pressure ( 25 ).…”

An Overview of Glycosylation and its Impact on Cardiovascular Health and Disease

“…O- glycosylations are subdivided into mucin-type and O -GlcNAcylation. Growing evidence supports different roles for glycosylation in CVDs: 1) for example the N- glycans attached to different glycoproteins that exhibit a critical role for cardiovascular function show N- glycosylation, such as IgG glycans patterns, which allowed distinguishing patients with dyslipidemia from the controls ( Liu et al, 2018 ); 2) changes in mucin-type O- glycosylation pattern in G protein-coupled receptors (GPCRs) are potential biomarkers in the pathogenesis of cardiac hypertrophy and heart failure (HF) ( Nagai-Okatani and Minamino, 2016 ; Goth et al, 2020 ); and 3) O -GlcNAcylation that could be beneficial or impair cell functioning, dependent on the microenvironment ( Ngoh et al, 2010 ; Jensen et al, 2019 ; Ng et al, 2021 ). This review aims to bring together research on the impact of N -glycosylation and O -glycosylation, including O- GlcNAcylation, on cardiovascular diseases.…”