Abstract 15249: Phosphoinositide 3-Kinase p110α Gene Therapy Ameliorates Diabetic Cardiomyopathy in Mice
Diabetic cardiomyopathy is characterised by left ventricular (LV) diastolic dysfunction accompanied by LV fibrosis and increases in levels of both cardiomyocyte apoptosis and reactive oxygen species. We tested the hypothesis that recombinant adeno-associated viral vector-6 carrying a constitutively active PI3K construct (rAAV6-caPI3K) gene therapy limits streptozotocin (STZ)-induced diabetic cardiomyopathy in mice. Diabetes was induced in male FVB/N mice by STZ (55mg/kg/day i.p for 5 days). After 8wks of diabetes, LV diastolic dysfunction was confirmed by Doppler echocardiography (impaired transmitral E/A). A single i.v. injection of rAAV6-caPI3K (2x1011 vector genomes) or null vector was then administered, and mice were followed for a further 6wks (cohort 1) or 8wks (cohort 2) after gene therapy (all n=7-10/group). Diabetes-induced LV fibrosis (collagen content) and apoptosis (TUNEL positive cells, Bax/Bcl2 ratio) were attenuated 6wks (cohort 1) after rAAV6-caPI3K (↓42±15%, ↓51±16%, ↓26±8%, respectively, all P<0.05) and remained attenuated 8wks (cohort 2) after gene delivery. These cardioprotective actions were accompanied by attenuation of LV dysfunction. Further improvements in LV function, both systolic (fractional shortening [FS] and velocity of circumferential fiber shortening [VcFc]) and diastolic function (deceleration time [DT] and isovolumic relaxation time [IVRT]) were evident 8wks after rAAV6-caPI3K (Table). Furthermore, diabetes-induced increase in LV protein levels of NADPH oxidase 2 and p22phox were also abolished by rAAV6-caPI3K gene therapy (↓32±14% and ↓36±12%, respectively, all P<0.05). Thus, these findings suggest that rAAV6-caPI3K administered at clinically-relevant time points (after diastolic dysfunction has manifested) may ultimately be a promising approach for treating diabetic cardiomyopathy.
Author Disclosures: D. Prakoso: None. M.J. De Blasio: None. C. Qin: None. S. Rosli: None. H. Kiriazis: None. H. Qian: None. X. Du: None. K.L. Weeks: None. P. Gregorevic: None. J.R. McMullen: None. R.H. Ritchie: None.
- © 2016 by American Heart Association, Inc.