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

Autor: Bedioune I; Université Paris-Saclay, 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.), Orsay, France., Gandon-Renard M; Université Paris-Saclay, 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.), Orsay, France., Dessillons M; Université Paris-Saclay, 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.), Orsay, France., Barthou A; Université Paris-Saclay, 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.), Orsay, France., Varin A; Université Paris-Saclay, 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.), Orsay, France., Mika D; Université Paris-Saclay, 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.), Orsay, France., Bichali S; Université Paris-Saclay, 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.), Orsay, France., Cellier J; Université Paris-Saclay, 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.), Orsay, France., Lechène P; 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Université Paris-Saclay, 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.), Orsay, France., Mercier-Nomé F; Université Paris-Saclay, Inserm, UMS IPSIT (F.M.-N.), Orsay, France., Mateo P; Université Paris-Saclay, 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.), Orsay, France., Dubourg A; Université Paris-Saclay, 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.), Orsay, France., 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.)., Mercadier JJ; Université Paris-Saclay, 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.), Orsay, France.; Xavier Bichat school of Medicine, Paris, France (J.-J.M.)., Benitah JP; Université Paris-Saclay, 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.), Orsay, France., Algalarrondo V; Université Paris-Saclay, 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.), Orsay, France., Leroy J; Université Paris-Saclay, 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.), Orsay, France., Fischmeister R; Université Paris-Saclay, 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.), Orsay, France., Gomez AM; Université Paris-Saclay, 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.), Orsay, France., Vandecasteele G; Université Paris-Saclay, 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.), Orsay, France.
Jazyk: angličtina
Zdroj: Circulation [Circulation] 2024 Dec 17; Vol. 150 (25), pp. 2031-2045. Date of Electronic Publication: 2024 Oct 02.
DOI: 10.1161/CIRCULATIONAHA.124.068858
Abstrakt: 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.
Competing Interests: Dr Stratakis holds patents on the PRKAR1A, phosphodiesterase 11A, and GPR101 molecules and their function. He is a recipient of funding from Pfizer, Inc for research on growth hormone and growth hormone–producing tumors. Dr Stratakis has working relationships with the ELPEN and H. Lundbeck A/S pharmaceutical companies. The other authors report no conflicts.
Databáze: MEDLINE
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