Cardiac gene therapy of heart failure with phosphodiesterase PDE4B in mice

Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): A. Bourcier, C. Coquard, J. Margaria, S. Gomez, A. Varin, A. Ghigo, V. Algalarrondo, G. Vandecasteele, E. Hirsch, R. Fischmeister, J. LeroyChronic 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 (1012 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 h...
Source: Archives of Cardiovascular Diseases Supplements - Category: Cardiology Source Type: research