Abstract 14989: Excessive Protein O-GlcNAcylation Contributes to the Development of Coronary Microvascular Disease in Type 2 Diabetic Mice.

Coronary artery disease and coronary microvascular disease are a leading cause of death in diabetic patients. However, the molecular mechanisms by which diabetes causes coronary microvascular dysfunction is not well understood. Protein O -GlcNAcylation is one of the posttranslational modifications and regulated by two enzymes; O -GlcNAc transferase catalyzes the addition of O -GlcNAc to the proteins and O -GlcNAcase (OGA) removes O -GlcNAc. We recently reported that increased protein O -GlcNAcylation attenuated endothelium-dependent vascular relaxation in type 1 diabetic mice. In this study, we investigate whether and how excessive protein O -GlcNAcylation leads to coronary microvascular dysfunction in type 2 diabetic (T2D) mice. We used endothelium-specific tetracycline-inducible OGA transgenic mice. T2D mice were generated by a single injection of low dose streptozotocin (75mg/kg, i.p.) with a high fat diet (60 % kcal from fat). Six weeks after T2D induction, doxycycline was administered in drinking water (0.2 mg/ml) for 6 weeks. T2D mice exhibited decreased coronary flow velocity reserve (CFVR, a marker of coronary microvascular dysfunction), increased EC apoptosis and decreased capillary density in the left ventricle (LV) compared to the control. OGA overexpression in T2D mice restored the level of EC apoptosis, capillary density, and CFVR toward control levels. T2D mice also exhibited attenuated cardiac contractility evidenced by decreased left ventricular systolic pressure, ejection fraction, and dp/dt. These parameters were increased by OGA overexpression in T2D mice. To investigate the target genes influenced by protein O -GlcNAcylation, we isolated mouse coronary ECs and performed a PCR Array. We revealed that Sp1 and Mapk1 were decreased in T2D mice and increased by OGA overexpression in T2D. Our results suggest that increased protein O -GlcNAcylation leads to coronary microvascular disease via increasing EC apoptosis. Overexpression of OGA in ECs not only restores coronary microvascular function, but also improves cardiac function. Further study on the role of Sp1 and Mapk1 in coronary microvascular disease might help develop novel treatment for coronary microvascular disease and cardiac dysfunction in type 2 diabetic patients. [ABSTRACT FROM AUTHOR]