Abstract 3331: Cardiac-Specific IGF-1 Receptor (IGF-1R) Transgenic Mice Are Protected Against Cardiac Fibrosis and Diastolic Dysfunction in Type 1 Diabetic Cardiomyopathy
Human diabetic cardiac disease is characterised by early diastolic dysfunction, often preceding impairments in systolic function. Left ventricular (LV) remodeling such as cardiomyocyte hypertrophy and fibrosis are also evident and underlie prolonged LV relaxation and delayed LV filling. Cardiac-specific IGF-1R signaling promotes protective physiological hypertrophy, with preservation of LV function and prevention of pathological LV remodeling, without risking IGF-1-induced adverse effects on extra-cardiac organs. The objective of the present study was to elucidate whether cardiac-specific transgenic (Tg) expression of IGF-1R specifically prevents diabetes-induced diastolic dysfunction, and explore the mechanisms of this protection. Male IGF-1R Tg and non-transgenic (Ntg) 7-wk old mice received streptozotocin (STZ, 55 mg/kg i.p./day for 5 days) or vehicle and diabetes allowed to progress 8 weeks. IGF-1R Tg mice were protected from diastolic dysfunction (on echocardiography-derived E/A ratio and deceleration time, as well as LV end-diastolic pressure, LV EDP) and cardiac fibrosis (LV collagen content and LV pro-collagen III expression), and this protection was associated with preservation of the cell-survival kinase Akt. LV systolic dysfunction was not evident in STZ mice. Diabetes was associated with cardiomyocyte hypertrophy, which was maintained in IGF-1R Tg mice. In conclusion, this study strongly suggests that cardiac-specific transgenic IGF-1R expression specifically protects against diastolic dysfunction (prior to the onset of systolic dysfunction), and that this protection is associated with decreased cardiac fibrosis and preserved Akt. Given that IGF-1R diabetic mice exhibit LV hypertrophy without fibrosis or dysfunction, IGF-1R expression may also protect the diabetic heart from pathological hypertrophy.