Essential Role of the RIα Subunit of cAMP-Dependent Protein Kinase in Regulating Cardiac Contractility and Heart Failure Development
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Le résumé fourni par la source
BACKGROUND: The heart expresses 2 main subtypes of cAMP-dependent protein kinase (PKA; type I and II) that differ in their regulatory subunits, RIα and RIIα. Embryonic lethality of RIα knockout mice limits the current understanding of type I PKA function in the myocardium. The objective of this study was to test the role of RIα in adult heart contractility and pathological remodeling. METHODS: We measured PKA subunit expression in human heart and developed a conditional mouse model with cardiomyocyte-specific knockout of RIα (RIα-icKO). Myocardial structure and function were evaluated by echocardiography, histology, and ECG and in Langendorff-perfused hearts. PKA activity and cAMP levels were determined by immunoassay, and phosphorylation of PKA targets was assessed by Western blot. L-type Ca 2+ current ( I Ca,L ), sarcomere shortening, Ca 2+ transients, Ca 2+ sparks and waves, and subcellular cAMP were recorded in isolated ventricular myocytes (VMs). RESULTS: RIα protein was decreased by 50% in failing human heart with ischemic cardiomyopathy and by 75% in the ventricles and in VMs from RIα-icKO mice but not in atria or sinoatrial node. Basal PKA activity was increased ≈3-fold in RIα-icKO VMs. In young RIα-icKO mice, left ventricular ejection fraction was increased and the negative inotropic effect of propranolol was prevented, whereas heart rate and the negative chronotropic effect of propranolol were not modified. Phosphorylation of phospholamban, ryanodine receptor, troponin I, and cardiac myosin-binding protein C at PKA sites was increased in propranolol-treated RIα-icKO mice. Hearts from RIα-icKO mice were hypercontractile, associated with increased I Ca,L, and [Ca 2+ ] i transients and sarcomere shortening in VMs. These effects were suppressed by the PKA inhibitor, H89. Global cAMP content was decreased in RIα-icKO hearts, whereas local cAMP at the phospholamban/sarcoplasmic reticulum Ca 2+ ATPase complex was unchanged in RIα-icKO VMs. RIα-icKO VMs had an increased frequency of Ca 2+ sparks and proarrhythmic Ca 2+ waves, and RIα-icKO mice had an increased susceptibility to ventricular tachycardia. On aging, RIα-icKO mice showed progressive contractile dysfunction, cardiac hypertrophy, and fibrosis, culminating in congestive heart failure with reduced ejection fraction that caused 50% mortality at 1 year. CONCLUSIONS: These results identify RIα as a key negative regulator of cardiac contractile function, arrhythmia, and pathological remodeling.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Essential Role of the RIα Subunit of cAMP-Dependent Protein Kinase in Regulating Cardiac Contractility and Heart Failure Development
- Date Crossref
- 17/12/2024
- Éditeur
- Ovid Technologies (Wolters Kluwer Health)
- Type
- journal-article
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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MACOM (United States) pays non établi dans la noticeEntreprise
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Inserm pays non établi dans la noticeOrganisme public
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Université Paris-Saclay G.V.) pays non établi dans la noticeUniversité ou école supérieure
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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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National Institutes of Health pays non établi dans la noticeOrganisme public
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Elpen Pharmaceutical (Greece) pays non établi dans la noticeEntreprise
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FORTH Institute of Molecular Biology and Biotechnology pays non établi dans la noticeStructure de recherche
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Eunice Kennedy Shriver National Institute of Child Health and Human Development pays non établi dans la noticeStructure de recherche
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Hôpital Xavier Arnozan pays non établi dans la noticeÉtablissement de santé
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ELPEN Research Institute pays non établi dans la noticeStructure de recherche
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Human Genetics and Precision Medicine pays non établi dans la noticeInstitution
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Xavier Bichat school of Medicine pays non établi dans la noticeUniversité ou école supérieure
MACOM (United States), Inserm et G.V.) — Université Paris-Saclay, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.