Essential Role of the RIα Subunit of cAMP-Dependent Protein Kinase in Regulating Cardiac Contractility and Heart Failure Development.

arrhythmias, cardiac calcium cyclic AMP-dependent protein kinases excitation contraction coupling heart protein kinases

Journal

Circulation
ISSN: 1524-4539
Titre abrégé: Circulation
Pays: United States
ID NLM: 0147763

Informations de publication

Date de publication:
02 Oct 2024
Historique:
medline: 2 10 2024
pubmed: 2 10 2024
entrez: 2 10 2024
Statut: aheadofprint

Résumé

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. 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 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 These results identify RIα as a key negative regulator of cardiac contractile function, arrhythmia, and pathological remodeling.

Sections du résumé

BACKGROUND UNASSIGNED
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 UNASSIGNED
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
RESULTS UNASSIGNED
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
CONCLUSIONS UNASSIGNED
These results identify RIα as a key negative regulator of cardiac contractile function, arrhythmia, and pathological remodeling.

Identifiants

DOI: 10.1161/CIRCULATIONAHA.124.068858 PMID: 39355927
pubmed: 39355927
doi: 10.1161/CIRCULATIONAHA.124.068858
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Auteurs

Ibrahim Bedioune (I)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.

Marine Gandon-Renard (M)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.
ORCID: 0000-0002-4862-036X

Matthieu Dessillons (M)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.

Aurélien Barthou (A)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.

Audrey Varin (A)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.
ORCID: 0009-0000-1709-2333

Delphine Mika (D)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.
ORCID: 0000-0003-2895-7173

Saïd Bichali (S)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.
ORCID: 0000-0003-2220-6061

Joffrey Cellier (J)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.
ORCID: 0000-0003-2667-4639

Patrick Lechène (P)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.
ORCID: 0000-0002-9194-0000

Sarah Karam (S)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.

Maya Dia (M)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.
ORCID: 0000-0001-6531-9176

Susana Gomez (S)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.
ORCID: 0000-0002-4890-0548

Walma Pereira de Vasconcelos (W)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.

Françoise Mercier-Nomé (F)

Inserm, UMS IPSIT (F.M.-N.), Université Paris-Saclay, Orsay, France.
ORCID: 0000-0002-9515-7232

Philippe Mateo (P)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.
ORCID: 0009-0005-1631-4615

Audrey Dubourg (A)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.
ORCID: 0000-0002-0213-1261

Constantine A Stratakis (CA)

Human Genetics and Precision Medicine, IMBB, FORTH, Heraklion, Crete, Greece (C.A.S.).
ELPEN Research Institute, Athens, Greece (C.A.S.).
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (C.A.S.).
ORCID: 0000-0002-4058-5520

Jean-Jacques Mercadier (JJ)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.
Xavier Bichat school of Medicine, Paris, France (J.-J.M.).
ORCID: 0000-0002-7398-0201

Jean-Pierre Benitah (JP)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.
ORCID: 0000-0002-9866-9081

Vincent Algalarrondo (V)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.
ORCID: 0000-0001-5971-1235

Jérôme Leroy (J)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.
ORCID: 0000-0001-5168-0606

Rodolphe Fischmeister (R)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.
ORCID: 0000-0003-2086-9865

Ana-Maria Gomez (AM)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.
ORCID: 0000-0003-0009-2884

Grégoire Vandecasteele (G)

Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S1180 (I.B., M.G.-R., M.D., A.B., A.V., D.M., S.B., J.C., P.L., S.K., M.D., S.G., W.P.d.V., P.M., A.D., J.-J.M., J.-P.B., V.A., J.L., R.F., A.-M.G., G.V.), Université Paris-Saclay, Orsay, France.
ORCID: 0000-0002-4046-4171

Classifications MeSH