Cardiac gene therapy with PDE2A limits remodeling and arrhythmias in mouse models of heart failure induced by catecholamines
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Le résumé fourni par la source
ABSTRACT BACKGROUND Constitutive cardiac PDE2 activation was shown to protect against contractile dysfunction and arrhythmia in heart failure (HF). However, it remains unknown whether an acute elevation of PDE2 is efficient to prevent maladaptive remodeling and arrhythmia. In this study we tested whether increasing acutely PDE2A activity in preclinical models of HF using cardiac PDE2 gene transfer could be of therapeutic value. METHODS AND RESULTS C57BL/6 male mice were injected with serotype 9 adeno-associated viruses (AAV9) encoding for PDE2A, or luciferase (LUC). Cardiac function assessed by echocardiography unveiled neither structural change nor dysfunction consecutive to PDE2A overexpression while AAV9 inoculation led to a ≈10-fold rise of PDE2A protein levels. Two weeks after AAV9 injections, mice were implanted with osmotic minipumps delivering NaCl or isoproterenol (Iso) (60 mg/kg/day) or Iso and phenylephrine (Iso+Phe, 30 mg/kg/day each) for 2 weeks. In LUC mice, chronic infusion with Iso increased left ventricular (LV) weight over body weight ratio, promoted fibrosis and decreased ejection fraction, but animals overexpressing PDE2A were protected towards these deleterious effects. Similarly, concomitant treatment with Iso+Phe promoted LV contractile dysfunction, fibrosis and apoptosis in LUC mice, while PDE2A overexpression limited these adverse outcomes. 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. Chronic treatment with catecholamines favoured spontaneous calcium waves upon β-AR stimulation at the cellular level and promoted susceptibility to ventricular arrhythmias in vivo evoked by catheter-mediated ventricular pacing after Iso and atropine injection. However, these adverse effects were blunted by the cardiac gene therapy with PDE2A. CONCLUSION Gene therapy with PDE2A limits cardiac adverse left ventricle remodeling and dysfunction induced by catecholamines as well as ventricular arrhythmias, providing evidence that acutely increasing PDE2A activity could prevent progression towards HF.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Cardiac gene therapy with PDE2A limits remodeling and arrhythmias in mouse models of heart failure induced by catecholamines
- Date Crossref
- 20/04/2023
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Inserm pays non établi dans la noticeOrganisme public
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Université Paris-Saclay pays non établi dans la noticeUniversité ou école supérieure
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Laboratory Signaling and Cardiovascular Pathophysiology pays non établi dans la noticeStructure de recherche
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Vita-Salute San Raffaele University pays non établi dans la noticeUniversité ou école supérieure
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University of Turin pays non établi dans la noticeUniversité ou école supérieure
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Centre National de la Recherche Scientifique pays non établi dans la noticeOrganisme public
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Institut du Thorax pays non établi dans la noticeStructure de recherche
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Ingénierie et Plateformes au Service de l'Innovation Thérapeutique pays non établi dans la noticeStructure de recherche
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Cystic Kidney Disorders Unit pays non établi dans la noticeInstitution
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University of Torino Department of Molecular Biotechnology and Health Sciences pays non établi dans la noticeUniversité ou école supérieure
Inserm, Université Paris-Saclay et Laboratory Signaling and Cardiovascular Pathophysiology, avec 7 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.