O-linked beta-N-acetylglucosamine transferase plays an essential role in heart development through regulating angiopoietin-1

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. Author summary As the first functional organ to form, the heart develops from a simple tube to a complex organ with four chambers to keep up with the body's increasing demand for blood. During this period, myocardium, the major component of heart, undergoes substantial dynamic architectural remodeling at different levels. This remodeling also coincides with coronary vessel development to form a functional heart. Defects in architectural remodeling of myocardium or coronary vessel development can lead to anatomical changes during heart development, resulting in congenital heart disease. O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) is the only enzyme catalyzing protein O-GlcNAcylation using UDP-GlcNAc, the end product of the hexosamine biosynthetic pathway. Hence, OGT is also considered a sensor of cellular nutrient levels. In this study, we found that loss of OGT in myocardium disrupted myocardial remodeling, as well as coronary vessel development, through regulating Angiopoietin-1 expression. Our study not only demonstrates an essential role for myocardial OGT during heart development, but also has potential implications for the development of new treatment options targeting coronary diseases.