Cardiac Gene Therapy With Phosphodiesterase 2A Limits Remodeling and Arrhythmias in Mouse Models of Heart Failure
Background PDE2 (phosphodiesterase 2) is upregulated in human heart failure. Cardiac PDE2‐transgenic mice are protected against contractile dysfunction and arrhythmias in heart failure but whether an acute elevation of PDE2 could be of therapeutic value remains elusive. This hypothesis was tested us...
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Wiley
2025-02-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.124.037343 |
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| author | Rima Kamel Aurélia Bourcier Jean Piero Margaria Valentin Jin Audrey Varin Agnès Hivonnait Françoise Mercier‐Nomé Delphine Mika Alessandra Ghigo Flavien Charpentier Vincent Algalarrondo Emilio Hirsch Rodolphe Fischmeister Grégoire Vandecasteele Jérôme Leroy |
| author_facet | Rima Kamel Aurélia Bourcier Jean Piero Margaria Valentin Jin Audrey Varin Agnès Hivonnait Françoise Mercier‐Nomé Delphine Mika Alessandra Ghigo Flavien Charpentier Vincent Algalarrondo Emilio Hirsch Rodolphe Fischmeister Grégoire Vandecasteele Jérôme Leroy |
| author_sort | Rima Kamel |
| collection | DOAJ |
| description | Background PDE2 (phosphodiesterase 2) is upregulated in human heart failure. Cardiac PDE2‐transgenic mice are protected against contractile dysfunction and arrhythmias in heart failure 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 heart failure. Methods and Results C57BL/6 male mice were injected with serotype 9 adeno‐associated viruses encoding for PDE2A. This led to a ≈10‐fold rise of PDE2A protein levels that affected neither cardiac structure nor function in healthy mice. Two weeks after inoculation with serotype 9 adeno‐associated viruses, mice were implanted with minipumps delivering either NaCl, isoproterenol (60 mg/kg per day), or isoproterenol and phenylephrine (30 mg/kg per day each) for 2 weeks. In mice injected with serotype 9 adeno‐associated viruses encoding for LUC (luciferase), isoproterenol or isoproterenol+phenylephrine infusion induced left ventricular hypertrophy, decreased ejection fraction unveiled by echocardiography, and promoted fibrosis and apoptosis assessed by Masson's trichrome and Tunel, respectively. Furthermore, inotropic responses to isoproterenol of ventricular cardiomyocytes isolated from isoproterenol+phenylephrine‐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 isoproterenol (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 evidence that increasing PDE2A activity acutely could prevent progression toward heart failure. |
| format | Article |
| id | doaj-art-57dea2adc75946d39511fb18a14cbcb7 |
| institution | Kabale University |
| issn | 2047-9980 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
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| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj-art-57dea2adc75946d39511fb18a14cbcb72025-02-04T11:00:01ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802025-02-0114310.1161/JAHA.124.037343Cardiac Gene Therapy With Phosphodiesterase 2A Limits Remodeling and Arrhythmias in Mouse Models of Heart FailureRima Kamel0Aurélia Bourcier1Jean Piero Margaria2Valentin Jin3Audrey Varin4Agnès Hivonnait5Françoise Mercier‐Nomé6Delphine Mika7Alessandra Ghigo8Flavien Charpentier9Vincent Algalarrondo10Emilio Hirsch11Rodolphe Fischmeister12Grégoire Vandecasteele13Jérôme Leroy14Université Paris‐Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR‐S 1180 Orsay FranceUniversité Paris‐Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR‐S 1180 Orsay FranceUniversité Paris‐Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR‐S 1180 Orsay FranceUniversité Paris‐Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR‐S 1180 Orsay FranceUniversité Paris‐Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR‐S 1180 Orsay FranceNantes Université, CNRS, INSERM, l’institut du thorax Nantes FranceUniversité Paris‐Saclay, Inserm US31, CNRS UMS3679, IPSIT Orsay FranceUniversité Paris‐Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR‐S 1180 Orsay FranceMolecular Biotechnology Center “Guido Tarone”, Department of Molecular Biotechnology and Health Sciences University of Torino ItalyNantes Université, CNRS, INSERM, l’institut du thorax Nantes FranceUniversité Paris‐Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR‐S 1180 Orsay FranceMolecular Biotechnology Center “Guido Tarone”, Department of Molecular Biotechnology and Health Sciences University of Torino ItalyUniversité Paris‐Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR‐S 1180 Orsay FranceUniversité Paris‐Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR‐S 1180 Orsay FranceUniversité Paris‐Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR‐S 1180 Orsay FranceBackground PDE2 (phosphodiesterase 2) is upregulated in human heart failure. Cardiac PDE2‐transgenic mice are protected against contractile dysfunction and arrhythmias in heart failure 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 heart failure. Methods and Results C57BL/6 male mice were injected with serotype 9 adeno‐associated viruses encoding for PDE2A. This led to a ≈10‐fold rise of PDE2A protein levels that affected neither cardiac structure nor function in healthy mice. Two weeks after inoculation with serotype 9 adeno‐associated viruses, mice were implanted with minipumps delivering either NaCl, isoproterenol (60 mg/kg per day), or isoproterenol and phenylephrine (30 mg/kg per day each) for 2 weeks. In mice injected with serotype 9 adeno‐associated viruses encoding for LUC (luciferase), isoproterenol or isoproterenol+phenylephrine infusion induced left ventricular hypertrophy, decreased ejection fraction unveiled by echocardiography, and promoted fibrosis and apoptosis assessed by Masson's trichrome and Tunel, respectively. Furthermore, inotropic responses to isoproterenol of ventricular cardiomyocytes isolated from isoproterenol+phenylephrine‐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 isoproterenol (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 evidence that increasing PDE2A activity acutely could prevent progression toward heart failure.https://www.ahajournals.org/doi/10.1161/JAHA.124.037343arrhythmiacAMP‐phosphodiesterasecatecholaminesexcitation‐contraction couplinggene therapyheart failure |
| spellingShingle | Rima Kamel Aurélia Bourcier Jean Piero Margaria Valentin Jin Audrey Varin Agnès Hivonnait Françoise Mercier‐Nomé Delphine Mika Alessandra Ghigo Flavien Charpentier Vincent Algalarrondo Emilio Hirsch Rodolphe Fischmeister Grégoire Vandecasteele Jérôme Leroy Cardiac Gene Therapy With Phosphodiesterase 2A Limits Remodeling and Arrhythmias in Mouse Models of Heart Failure Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease arrhythmia cAMP‐phosphodiesterase catecholamines excitation‐contraction coupling gene therapy heart failure |
| title | Cardiac Gene Therapy With Phosphodiesterase 2A Limits Remodeling and Arrhythmias in Mouse Models of Heart Failure |
| title_full | Cardiac Gene Therapy With Phosphodiesterase 2A Limits Remodeling and Arrhythmias in Mouse Models of Heart Failure |
| title_fullStr | Cardiac Gene Therapy With Phosphodiesterase 2A Limits Remodeling and Arrhythmias in Mouse Models of Heart Failure |
| title_full_unstemmed | Cardiac Gene Therapy With Phosphodiesterase 2A Limits Remodeling and Arrhythmias in Mouse Models of Heart Failure |
| title_short | Cardiac Gene Therapy With Phosphodiesterase 2A Limits Remodeling and Arrhythmias in Mouse Models of Heart Failure |
| title_sort | cardiac gene therapy with phosphodiesterase 2a limits remodeling and arrhythmias in mouse models of heart failure |
| topic | arrhythmia cAMP‐phosphodiesterase catecholamines excitation‐contraction coupling gene therapy heart failure |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.124.037343 |
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