O‐GlcNacase overexpression restores coronary endothelial dysfunction in type 1 diabetic mice (1076.1)

Abstract

Cardiac ischemia is a leading cause of morbidity and mortality in diabetes, and endothelial cell (EC) dysfunction is implicated in coronary arterial disease. O‐linked N‐acetyglucosamine (O‐GlcNAcylation) is a post‐translational modification that is tightly controlled by two enzymes: O‐GlcNAc transferase (OGT, catalyzes the addition of an O‐GlcNAc to proteins) and O‐GlcNAcase (GCA, removes GlcNAc from proteins). In this study, we examine the role of GCA in coronary endothelial dysfunction in type 1 diabetic mice.We generated EC‐specific, inducible GCA transgenic mice and induced diabetes in these mice with streptozotocin. In diabetic mouse coronary endothelial cells (MCECs), GCA expression was significantly decreased and protein O‐GlcNAcylation was increased. GCA overexpression in diabetic mice decreased O‐GlcNAcylation in MCECs. Capillary density in the left ventricle was decreased in diabetes, while GCA overexpression significantly increased the density to the control level. Endothelium‐dependent relaxation was attenuated in diabetic coronary arteries (CAs) and restored by GCA overexpression. These data suggest that elevated protein O‐GlcNAcylation due to decreased GCA protein expression in MCECs contributes to coronary endothelial dysfunction in diabetes, whereas overexpression of GCA in ECs improves endothelial function and may have a beneficial effect on coronary vascular complications in diabetes.Grant Funding Source: supported by NIH/NHLBI(HL115578)