Cardiac gene therapy of heart failure with phosphodiesterase PDE4B in mice

Abstract

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 < 0.0001), increased left ventricular weight/body weight ratio (LVW/BW, + 86.7 ± 15.7%, N = 6, P < 0.0001). Although PDE4B overexpression did not ameliorate EF, it delayed the decrease of EF at 2 weeks ( N = 9, P < 0.05), prevented LV hypertrophy ( N = 9, P < 0.001) and fibrosis ( N = 9, P < 0.05). Chronic Iso and Phe treatment induced LV hypertrophy (LVW/BW, + 37.8 ± 6.2%, N = 7, P < 0.001) and decreased EF (- 25 ± 3.5%, N = 7, P < 0.0001). While PDE4B overexpression only slightly ameliorated EF (- 17 ± 3%, N = 9) in this model, LV hypertrophy was significantly diminished ( N = 9, P < 0.05). PDE4B protein level was assessed by western blotting and revealed a ∼6 to 9-fold increased expression in both HF models. We are currently analyzing whether PDE4B overexpression can prevent fibrosis induced by catecholamines and limit ventricular arrhythmias induced by catheter-mediated burst pacing following intraperitoneal injection of isoprenaline. Altogether, our preliminary results suggest that gene therapy with PDE. Chronic ß-AR activation is detrimental because it promotes cardiac remodeling and ultimately leads to heart failure (HF). Multiple cyclic nucleotide phosphodiesterases (PDEs) finely tune ß-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 < 0.0001), increased left ventricular weight/body weight ratio (LVW/BW, + 86.7 ± 15.7%, N = 6, P < 0.0001). Although PDE4B overexpression did not ameliorate EF, it delayed the decrease of EF at 2 weeks ( N = 9, P < 0.05), prevented LV hypertrophy ( N = 9, P < 0.001) and fibrosis ( N = 9, P < 0.05). Chronic Iso and Phe treatment induced LV hypertrophy (LVW/BW, + 37.8 ± 6.2%, N = 7, P < 0.001) and decreased EF (- 25 ± 3.5%, N = 7, P < 0.0001). While PDE4B overexpression only slightly ameliorated EF (- 17 ± 3%, N = 9) in this model, LV hypertrophy was significantly diminished ( N = 9, P < 0.05). PDE4B protein level was assessed by western blotting and revealed a ∼6 to 9-fold increased expression in both HF models. We are currently analyzing whether PDE4B overexpression can prevent fibrosis induced by catecholamines and limit ventricular arrhythmias induced by catheter-mediated burst pacing following intraperitoneal injection of isoprenaline. Altogether, our preliminary results suggest that gene therapy with PDE4B is a potential therapeutic approach for cardiac maladaptive hypertrophy.4B is a potential therapeutic approach for cardiac maladaptive hypertrophy.