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

BACKGROUND: Diabetes mellitus is associated with increased risk of heart failure. We previously demonstrated in mice that a single injection of adeno-associated virus 8 encoding urocortin 2 (AAV8.UCn2) increases glucose disposal in models of insulin resistance and improves function of the failing heart. In the present study, we tested the hypothesis that UCn2 gene transfer would reduce diabetes-related left ventricular (LV) dysfunction.

METHODS: 8-week-old C57BL6 male mice fed a Western diet (WD; 45% fat, 35% carbohydrate) for 40 weeks. At week 30, they received saline or AAV8.UCn2 (2x1013 genome copy/kg) via intravenous injection. Ten weeks after gene transfer, we measured fasting blood glucose, glucose tolerance, and cardiac function via echocardiography and in vivo measurement of LV contractile function vs mice on normal chow (NC; 10% fat; 45% carbohydrate). We also measured contents of key LV signaling proteins to probe mechanisms.

RESULTS: The WD increased 12h fasting glucose (WD: 190±11 mg/dL, n=8; NC: 105±12mg/dL, n=7; p=.0002). WD reduced LV peak +dP/dt (p=.042) and LV peak -dP/dt (p=.027); LV ejection fraction was unchanged. Among mice fed WD, UCn2 gene transfer reduced 12h fasting glucose (WD-UCn2: 149±6 mg/dL, n=8; WD-Saline: 190±11 mg/dL, n=8; p=.006), and increased LV peak +dP/dt (p=.005) and LV peak -dP/dt (p=.007), and reduced Tau (p=.016), indicating beneficial effects on systolic and diastolic LV function. In addition, among WD-fed mice, UCn2 gene transfer increased LV EF (p=.005) and the velocity of circumferential fiber shortening (p=.0005). Finally, we saw reduction in fatty infiltration of liver in WD-fed mice that had received UCn2 gene transfer. LV samples from WD-UCn2 mice showed increased phosphorylation of PKA catalytic domain (p=.03).

CONCLUSIONS: UCn2 gene transfer increased LV systolic and diastolic function and reduced blood glucose in mice with diabetes-related LV dysfunction, indicating that UCn2 gene transfer may be of potential therapeutic benefit.