{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T05:00:52Z","timestamp":1789189252100,"version":"build-2803163510"},"reference-count":56,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"25","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2024,12,17]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>The heart expresses 2 main subtypes of cAMP-dependent protein kinase (PKA; type I and II) that differ in their regulatory subunits, RI\u03b1 and RII\u03b1. Embryonic lethality of RI\u03b1 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 RI\u03b1 in adult heart contractility and pathological remodeling.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              We measured PKA subunit expression in human heart and developed a conditional mouse model with cardiomyocyte-specific knockout of RI\u03b1 (RI\u03b1-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\n              <jats:sup>2+<\/jats:sup>\n              current (\n              <jats:italic toggle=\"yes\">I<\/jats:italic>\n              <jats:sub>Ca,L<\/jats:sub>\n              ), sarcomere shortening, Ca\n              <jats:sup>2+<\/jats:sup>\n              transients, Ca\n              <jats:sup>2+<\/jats:sup>\n              sparks and waves, and subcellular cAMP were recorded in isolated ventricular myocytes (VMs).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              RI\u03b1 protein was decreased by 50% in failing human heart with ischemic cardiomyopathy and by 75% in the ventricles and in VMs from RI\u03b1-icKO mice but not in atria or sinoatrial node. Basal PKA activity was increased \u22483-fold in RI\u03b1-icKO VMs. In young RI\u03b1-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 RI\u03b1-icKO mice. Hearts from RI\u03b1-icKO mice were hypercontractile, associated with increased\n              <jats:italic toggle=\"yes\">I<\/jats:italic>\n              <jats:sub>Ca,L,<\/jats:sub>\n              and [Ca\n              <jats:sup>2+<\/jats:sup>\n              ]\n              <jats:sub>i<\/jats:sub>\n              transients and sarcomere shortening in VMs. These effects were suppressed by the PKA inhibitor, H89. Global cAMP content was decreased in RI\u03b1-icKO hearts, whereas local cAMP at the phospholamban\/sarcoplasmic reticulum Ca\n              <jats:sup>2+<\/jats:sup>\n              ATPase complex was unchanged in RI\u03b1-icKO VMs. RI\u03b1-icKO VMs had an increased frequency of Ca\n              <jats:sup>2+<\/jats:sup>\n              sparks and proarrhythmic Ca\n              <jats:sup>2+<\/jats:sup>\n              waves, and RI\u03b1-icKO mice had an increased susceptibility to ventricular tachycardia. On aging, RI\u03b1-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.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>These results identify RI\u03b1 as a key negative regulator of cardiac contractile function, arrhythmia, and pathological remodeling.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.124.068858","type":"journal-article","created":{"date-parts":[[2024,10,2]],"date-time":"2024-10-02T09:01:06Z","timestamp":1727859666000},"page":"2031-2045","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":11,"title":["Essential Role of the RI\u03b1 Subunit of cAMP-Dependent Protein Kinase in Regulating Cardiac Contractility and Heart Failure Development"],"prefix":"10.1161","volume":"150","author":[{"given":"Ibrahim","family":"Bedioune","sequence":"first","affiliation":[{"name":"Universit\u00e9 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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4862-036X","authenticated-orcid":true,"given":"Marine","family":"Gandon-Renard","sequence":"additional","affiliation":[{"name":"Universit\u00e9 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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthieu","family":"Dessillons","sequence":"additional","affiliation":[{"name":"Universit\u00e9 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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lien","family":"Barthou","sequence":"additional","affiliation":[{"name":"Universit\u00e9 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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1709-2333","authenticated-orcid":true,"given":"Audrey","family":"Varin","sequence":"additional","affiliation":[{"name":"Universit\u00e9 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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2895-7173","authenticated-orcid":true,"given":"Delphine","family":"Mika","sequence":"additional","affiliation":[{"name":"Universit\u00e9 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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2220-6061","authenticated-orcid":true,"given":"Sa\u00efd","family":"Bichali","sequence":"additional","affiliation":[{"name":"Universit\u00e9 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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2667-4639","authenticated-orcid":true,"given":"Joffrey","family":"Cellier","sequence":"additional","affiliation":[{"name":"Universit\u00e9 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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9194-0000","authenticated-orcid":true,"given":"Patrick","family":"Lech\u00e8ne","sequence":"additional","affiliation":[{"name":"Universit\u00e9 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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Karam","sequence":"additional","affiliation":[{"name":"Universit\u00e9 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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6531-9176","authenticated-orcid":true,"given":"Maya","family":"Dia","sequence":"additional","affiliation":[{"name":"Universit\u00e9 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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4890-0548","authenticated-orcid":true,"given":"Susana","family":"Gomez","sequence":"additional","affiliation":[{"name":"Universit\u00e9 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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walma","family":"Pereira de Vasconcelos","sequence":"additional","affiliation":[{"name":"Universit\u00e9 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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9515-7232","authenticated-orcid":true,"given":"Fran\u00e7oise","family":"Mercier-Nom\u00e9","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, UMS IPSIT (F.M.-N.), Orsay, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1631-4615","authenticated-orcid":true,"given":"Philippe","family":"Mateo","sequence":"additional","affiliation":[{"name":"Universit\u00e9 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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0213-1261","authenticated-orcid":true,"given":"Audrey","family":"Dubourg","sequence":"additional","affiliation":[{"name":"Universit\u00e9 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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4058-5520","authenticated-orcid":true,"given":"Constantine A.","family":"Stratakis","sequence":"additional","affiliation":[{"name":"Human Genetics and Precision Medicine, IMBB, FORTH, Heraklion, Crete, Greece (C.A.S.)."},{"name":"ELPEN Research Institute, Athens, Greece (C.A.S.)."},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (C.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7398-0201","authenticated-orcid":true,"given":"Jean-Jacques","family":"Mercadier","sequence":"additional","affiliation":[{"name":"Universit\u00e9 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."},{"name":"Xavier Bichat school of Medicine, Paris, France (J.-J.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9866-9081","authenticated-orcid":true,"given":"Jean-Pierre","family":"Benitah","sequence":"additional","affiliation":[{"name":"Universit\u00e9 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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5971-1235","authenticated-orcid":true,"given":"Vincent","family":"Algalarrondo","sequence":"additional","affiliation":[{"name":"Universit\u00e9 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, 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