Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure
| العنوان: | Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure |
|---|---|
| المؤلفون: | Delphine Mika, V. Algalarrondo, Valérie Domergue, Aurelia Bourcier, Matthieu Dessillons, Pauline Robert, Kaouter Bouadjel, Jérôme Leroy, Philippe Mateo, Marta Lindner, Florence Lefebvre, Jean-Baptiste Michel, A. Varin, Flavien Charpentier, Rodolphe Fischmeister, Jean Piero Margaria, Jane-Lise Samuel, Ibrahim Bedioune, Sarah Karam, Patrick Lechêne, Susana Gomez, Emilio Hirsch, Françoise Gaudin, Grégoire Vandecasteele, Charlène Coquard, Alessandra Ghigo |
| المساهمون: | Signalisation et physiopathologie cardiovasculaire (CARPAT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Department of Molecular Biotechnologies and Health Sciences [Torino, Italy] (Hematology Division), Università degli studi di Torino (UNITO), Ingénierie et Plateformes au Service de l'Innovation Thérapeutique (IPSIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Université Sorbonne Paris Nord, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, FISCHMEISTER, RODOLPHE, Università degli studi di Torino = University of Turin (UNITO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN) |
| المصدر: | Circulation Circulation, American Heart Association, 2020, 142 (2), pp.161-174. ⟨10.1161/CIRCULATIONAHA.119.042573⟩ Circulation, 2020, 142 (2), pp.161-174. ⟨10.1161/CIRCULATIONAHA.119.042573⟩ |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Genetic enhancement, Gene Expression, heart failure, 030204 cardiovascular system & hematology, phosphodiesterase 4, Negative regulator, chemistry.chemical_compound, Mice, 0302 clinical medicine, PDE4B, Transduction, Genetic, Myocytes, Cardiac, 0303 health sciences, Ventricular Remodeling, cardiac remodeling, cyclic AMP, genetic therapy, transgenic mice, Phosphodiesterase, Adrenergic beta-Agonists, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Phenotype, Heart Function Tests, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Disease Susceptibility, Cardiology and Cardiovascular Medicine, Genetically modified mouse, Adenosine monophosphate, medicine.medical_specialty, Genetic Vectors, Mice, Transgenic, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Physiology (medical), Internal medicine, Receptors, Adrenergic, beta, medicine, Animals, Humans, 030304 developmental biology, business.industry, Myocardium, Isoproterenol, β adrenergic, medicine.disease, Cyclic Nucleotide Phosphodiesterases, Type 4, Disease Models, Animal, Endocrinology, chemistry, Heart failure, business |
| الوصف: | Background: The cyclic AMP (adenosine monophosphate; cAMP)-hydrolyzing protein PDE4B (phosphodiesterase 4B) is a key negative regulator of cardiac β-adrenergic receptor stimulation. PDE4B deficiency leads to abnormal Ca 2+ handling and PDE4B is decreased in pressure overload hypertrophy, suggesting that increasing PDE4B in the heart is beneficial in heart failure. Methods: We measured PDE4B expression in human cardiac tissues and developed 2 transgenic mouse lines with cardiomyocyte-specific overexpression of PDE4B and an adeno-associated virus serotype 9 encoding PDE4B. Myocardial structure and function were evaluated by echocardiography, ECG, and in Langendorff-perfused hearts. Also, cAMP and PKA (cAMP dependent protein kinase) activity were monitored by Förster resonance energy transfer, L-type Ca 2+ current by whole-cell patch-clamp, and cardiomyocyte shortening and Ca 2+ transients with an Ionoptix system. Heart failure was induced by 2 weeks infusion of isoproterenol or transverse aortic constriction. Cardiac remodeling was evaluated by serial echocardiography, morphometric analysis, and histology. Results: PDE4B protein was decreased in human failing hearts. The first PDE4B-transgenic mouse line (TG15) had a ≈15-fold increase in cardiac cAMP-PDE activity and a ≈30% decrease in cAMP content and fractional shortening associated with a mild cardiac hypertrophy that resorbed with age. Basal ex vivo myocardial function was unchanged, but β-adrenergic receptor stimulation of cardiac inotropy, cAMP, PKA, L-type Ca 2+ current, Ca 2+ transients, and cell contraction were blunted. Endurance capacity and life expectancy were normal. Moreover, these mice were protected from systolic dysfunction, hypertrophy, lung congestion, and fibrosis induced by chronic isoproterenol treatment. In the second PDE4B-transgenic mouse line (TG50), markedly higher PDE4B overexpression, resulting in a ≈50-fold increase in cardiac cAMP-PDE activity caused a ≈50% decrease in fractional shortening, hypertrophy, dilatation, and premature death. In contrast, mice injected with adeno-associated virus serotype 9 encoding PDE4B (10 12 viral particles/mouse) had a ≈50% increase in cardiac cAMP-PDE activity, which did not modify basal cardiac function but efficiently prevented systolic dysfunction, apoptosis, and fibrosis, while attenuating hypertrophy induced by chronic isoproterenol infusion. Similarly, adeno-associated virus serotype 9 encoding PDE4B slowed contractile deterioration, attenuated hypertrophy and lung congestion, and prevented apoptosis and fibrotic remodeling in transverse aortic constriction. Conclusions: Our results indicate that a moderate increase in PDE4B is cardioprotective and suggest that cardiac gene therapy with PDE4B might constitute a new promising approach to treat heart failure. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 0009-7322 1524-4539 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::787623791718c74dce9c7a27212f58c3 http://hdl.handle.net/2318/1765893 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....787623791718c74dce9c7a27212f58c3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00097322 15244539 |
|---|