5213Manipulation of cardiac O-GlcNAc modification alters cardiac function and remodelling in the setting of diabetic cardiomyopathy

Background: Glucose driven β-N-acetylglucosamine (O-GlcNAc) post-translational modification has been implicated in the development and progression of diabetic cardiomyopathy. Two enzymes regulate this post-translational modification: O-GlcNAc transferase (OGT) facilitates the addition of the O-GlcNAc sugar moiety to Ser/Thr residues, and O-GlcNAcase (OGA) facilitates its removal. Purpose: To study the impact of cardiac manipulation of O-GlcNAc signalling using cardiac-targeted OGA and OGT adeno-associated viral (AAV) gene delivery in the setting of diabetic cardiomyopathy. Methods: Diabetes was induced in 6wk-old male mice using streptozotocin (55mg/kg/day i.p./day, 5day). After 8wks of diabetes, LV diastolic dysfunction was confirmed by echocardiography. A single i.v. injection of rAAV6-OGT, rAAV6-OGA, null vector (all 2x1011vg) or high dose rAAV6-OGA (1x1012vg) was administered, and mice were followed for a further 8wks, prior to detailed in-vivo/ex-vivo analyses. Results: Administration of rAAV6-OGT to sham mice led to impaired diastolic function and cardiac remodelling, which included cardiac fibrosis and increased hypertrophic genes (β-myosin heavy chain and ANP) resembling the characteristics of diabetic cardiomyopathy. In contrast, administration of rAAV6-OGA to diabetic mice attenuated LV diastolic dysfunction and cardiac remodelling, with a more marked improvement in the high-dose treated group (Table 1).