Cardiac gene therapy of heart failure with phosphodiesterase PDE4B in mice

Chronic beta-AR activation is detrimental because it promotes cardiac remodeling and ultimately leads to heart failure (HF). Multiple cyclic nucleotide phosphodiesterases (PDEs) finely tune beta-AR responses by degrading and compartmentalizing cAMP. Since chronic treatment with PDE inhibitors increases mortality in HF, we postulated that decreasing cAMP levels by overexpressing PDE4B in the heart may have therapeutic effects. To test this hypothesis, we explored whether AAV9-mediated cardiac overexpression of PDE4B (10 12 viral particles) could prevent maladaptive hypertrophy in mice subjected either to transverse aortic constriction (TAC) for 6 weeks or 2 weeks isoproterenol (Iso) and phenylephrine (Phe) infusion (30μg/g/day each). Cardiac function was assessed by echocardiography. In control mice injected with a Luciferase-AAV9 (LUC), TAC decreased ejection fraction (EF, - 34.2 ± 6%, N  = 6, P N  = 6, P N  = 9, P N  = 9, P N  = 9, P N  = 7, P N  = 7, P N  = 9) in this model, LV hypertrophy was significantly diminished ( N  = 9, P 12 viral particles) could prevent maladaptive hypertrophy in mice subjected either to transverse aortic constriction (TAC) for 6 weeks or 2 weeks isoproterenol (Iso) and phenylephrine (Phe) infusion (30μg/g/day each). Cardiac function was assessed by echocardiography. In control mice injected with a Luciferase-AAV9 (LUC), TAC decreased ejection fraction (EF, -34.2 ± 6%, N  = 6, P N  = 6, P N  = 9, P N  = 9, P N  = 9, P N  = 7, P N  = 7, P N  = 9) in this model, LV hypertrophy was significantly diminished ( N  = 9, P