Abstract
O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) is the only enzyme catalyzing O-GlcNAcylation. Although it has been shown that OGT plays an essential role in maintaining postnatal heart function, its role in heart development remains unknown. Here we showed that loss of OGT in early fetal cardiomyocytes led to multiple heart developmental defects including hypertrabeculation, biventricular dilation, atrial septal defects, ventricular septal defects, and defects in coronary vessel development. In addition, RNA sequencing revealed that Angiopoietin-1, required within cardiomyocytes for both myocardial and coronary vessel development, was dramatically downregulated in cardiomyocyte-specific OGT knockout mouse hearts. In conclusion, our data demonstrated that OGT plays an essential role in regulating heart development through activating expression of cardiomyocyte Angiopoietin-1.
Highlights
O-GlcNAcylation is a post-translational modification that occurs by the addition of single Olinked β-N-acetylglucosamine (O-GlcNAc) moieties to serine or threonine residues, in a manner analogous to that of protein phosphorylation
Defects in architectural remodeling of myocardium or coronary vessel development can lead to anatomical changes during heart development, resulting in congenital heart disease
We found that loss of O-GlcNAc transferase (OGT) in myocardium disrupted myocardial remodeling, as well as coronary vessel development, through regulating Angiopoietin-1 expression
Summary
O-GlcNAcylation is a post-translational modification that occurs by the addition of single Olinked β-N-acetylglucosamine (O-GlcNAc) moieties to serine or threonine residues, in a manner analogous to that of protein phosphorylation. Global increases in O-GlcNAcylation have been reported in heart samples of patients with aortic stenosis, and similar observations have been made in rat models of heart failure induced by hypertension, myocardial infarction, or aortic constriction [8]. Data from both in vitro and in vivo models suggest that increased O-GlcNAcylation plays a cardioprotective role in settings of acute cardiac dysfunction, such as ischemia-reperfusion and traumahemorrhage, while O-GlcNAcylation may show deleterious effects on cardiac function in chronic conditions such as diabetic cardiomyopathy [6]. The role of OGT and O-GlcNAcylation during early heart development remains unclear
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