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Cardiac Gene Therapy with PDE2A Limits Remodeling and Arrhythmias in Mouse Models of Heart Failure
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Edité par CCSD ; Wiley-Blackwell -
International audience. BACKGROUND: Phosphodiesterase 2 (PDE2) is upregulated in human heart failure (HF). Cardiac PDE2-transgenic mice are protected against contractile dysfunction and arrhythmias in HF but whether an acute elevation of PDE2 could be of therapeutic value remains elusive. This hypothesis was tested using cardiac PDE2 gene transfer in preclinical models of HF.
METHODS AND RESULTS: C57BL/6 male mice were injected with serotype 9 adeno-associated viruses (AAV9) encoding for PDE2A. This led to a ≈10-fold rise of PDE2A protein levels which affected neither cardiac structure nor function in healthy mice. Two weeks after AAV9 inoculation, mice were implanted with minipumps delivering either NaCl, isoproterenol (Iso) (60 mg/kg/day) or Iso and phenylephrine (Iso+Phe, 30 mg/kg/day each) for 2 weeks. In mice injected with AAV9 encoding for luciferase (LUC), Iso or Iso+Phe infusion induced left ventricular hypertrophy, decreased ejection fraction unveiled by echocardiography, promoted fibrosis and apoptosis assessed by Masson's trichrome and Tunel, respectively. Furthermore, inotropic responses to Iso of ventricular cardiomyocytes isolated from Iso+Phe-LUC mice loaded with 1 µmol/L Fura-2AM and stimulated at 1 Hz to record calcium transients and sarcomere shortening were dampened. Spontaneous calcium waves at the cellular level were promoted as well as ventricular arrhythmias evoked in vivo by catheter-mediated ventricular pacing after Iso (1.5 mg/kg) and atropine (1 mg/kg) injection. However, increased PDE2A blunted these adverse outcomes evoked by sympathomimetic amines.
CONCLUSIONS: Cardiac gene therapy with PDE2A limits left ventricle remodeling, dysfunction and arrhythmias evoked by catecholamines, providing evidences that increasing PDE2A activity acutely could prevent progression towards HF.
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