Abstract 15267: Cardiac-Specific Insulin-Like Growth Factor-1 Receptor (IGF-1R) Expression Targets Maladaptive Hexosamine Biosynthesis and O-Linked GlcNAc Modification of Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA2a) in Diabetic Myocardium
Diabetes-induced cardiac complications include left ventricular (LV) fibrosis and dysfunction. Progression of “diabetic cardiomyopathy” has been linked to altered activation of the hexosamine biosynthesis pathway (HBP). Cardiac-specific IGF-1R transgenic (Tg) expression is cardioprotective against several cardiac pathologies, but its impact on maladaptive HBP and protein O-GlcNAcylation in the context of chronic diabetes has not been sought. We hypothesised that cardiac-specific IGF-1R Tg mice are protected against diabetes-induced upregulation of LV HBP in a mouse model of diabetic cardiomyopathy. Diabetes was induced in 6-week-old non-transgenic (Ntg) and IGF-1R Tg male mice via streptozotocin (STZ; 55mg/kg, or citrate buffer vehicle, CIT; i.p. for 5 consecutive days) and followed for a further 12 weeks. Cardiac IGF-1R attenuates diabetes-induced diastolic dysfunction (E/A ratio) and upregulation of LV NADPH oxidase and oxidative stress (superoxide, Nox2, 3-nitrotyrosine) (Table). Cardiac IGF-1R also limits diabetes-induced upregulation of the LV HBP/O-GlcNAc response (OGT, GFAT1, GFAT2), including O-linked GlcNAc modification of LV SERCA2a via immunoprecipitation (Table). Our results suggest that maladaptive LV glucose metabolism in the HBP is a therapeutic target in diabetes. Further, cardiac IGF-1R signalling represents a potential mechanism by which to limit detrimental progression of O-linked GlcNAc modification in the diabetic heart.
Author Disclosures: M.J. De Blasio: None. D. Prakoso: None. C. Qin: None. S. Rosli: None. H. Kiriazis: None. X. Du: None. J.C. Chatham: None. J.R. McMullen: None. R.H. Ritchie: None.
- © 2016 by American Heart Association, Inc.