Abstract 16670: Urocortin 2 Gene Transfer Reduces the Adverse Effects of Western Diet on Cardiac Function in Mice

Abstract

Diabetes mellitus increases the risk of heart failure. We previously showed that injection of adeno-associated virus 8 encoding urocortin 2 (AAV8.UCn2) increases glucose disposal in insulin resistance and improves function of the failing heart in mice. In the present study, we tested the hypothesis that UCn2 gene transfer would have beneficial effects in diabetic cardiomyopathy. Eight-week-old C57Bl/6J male mice were fed normal chow (NC) or a Western diet (WD, 35% kcal carbohydrate and 45% fat) for 30w, and then received saline or AAV8.UCn2 (1.9x10 13 genome copy/kg) via intravenous injection. Before and 10w after gene transfer, we measured fasting blood glucose, glucose tolerance, and cardiac function via echocardiography and rates of LV pressure development (+dP/dt) and decline (-dP/dt) using micromanometers. We also measured key signaling proteins in the left ventricle (LV). Western diet increased 12h fasting glucose levels compared to normal chow (81% increase; p<.0002). WD vs normal chow reduced LV peak +dP/dt (p=.042) and LV peak -dP/dt (p=.027), although LV ejection fraction (EF) was unchanged. Thus WD induced diabetes and cardiomyopathy with normal EF. Among mice fed WD, UCn2 gene transfer reduced fasting glucose (WD+Saline: 190±11 mg/dL, n=8; WD+UCn2: 149±6 mg/dL, n=8; p=.006), increased LV peak +dP/dt (p=.005; Fig A ), LV peak -dP/dt (p=.007; Fig B ), and reduced Tau (p=.016; Fig C ). In addition, among WD-fed mice, UCn2 gene transfer increased LV EF (p=.005) and the velocity of circumferential fiber shortening (p=.0005). LV samples from WD+UCn2 mice showed increased phosphorylation of PKA catalytic domain (WD+Saline: .2±.04, n=5; WD+UCn2: .3±.02, n=5; p=.03). In conclusion, UCn2 gene transfer increased LV systolic and diastolic function and reduced blood glucose in mice with diabetic cardiomyopathy.