{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T13:43:27Z","timestamp":1790171007244,"version":"4.1.0"},"reference-count":28,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2017,5]]},"abstract":"<jats:sec>\n                    <jats:title>Background\u2014<\/jats:title>\n                    <jats:p>Considerable evidence suggests that calcium\/calmodulin-dependent protein kinase II (CaMKII) overactivity plays a crucial role in the pathophysiology of heart failure (HF), a condition characterized by excessive \u03b2-adrenoceptor (\u03b2-AR) stimulation. Recent studies indicate a significant cross talk between \u03b2-AR signaling and CaMKII activation presenting CaMKII as a possible downstream mediator of detrimental \u03b2-AR signaling in HF. In this study, we investigated the effect of chronic \u03b2-AR blocker treatment on CaMKII activity in human and experimental HF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results\u2014<\/jats:title>\n                    <jats:p>\n                      Immunoblot analysis of myocardium from end-stage HF patients (n=12) and non-HF subjects undergoing cardiac surgery (n=12) treated with \u03b2-AR blockers revealed no difference in CaMKII activity when compared with non\u2013\u03b2-AR blocker\u2013treated patients. CaMKII activity was judged by analysis of CaMKII expression, autophosphorylation, and oxidation and by investigating the phosphorylation status of CaMKII downstream targets. To further evaluate these findings, CaMKII\u03b4\n                      <jats:sub>C<\/jats:sub>\n                      transgenic mice were treated with the \u03b2\n                      <jats:sub>1<\/jats:sub>\n                      -AR blocker metoprolol (270 mg\/kg*d). Metoprolol significantly reduced transgene-associated mortality (n\u226529;\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.001), attenuated the development of cardiac hypertrophy (\u221214\u00b16% heart weight\/tibia length;\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.05), and strongly reduced ventricular arrhythmias (\u221270\u00b122% premature ventricular contractions;\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.05). On a molecular level, metoprolol expectedly decreased protein kinase A\u2013dependent phospholamban and ryanodine receptor 2 phosphorylation (\u221242\u00b19% for P-phospholamban-S16 and \u221222\u00b17% for P-ryanodine receptor 2-S2808;\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.05). However, this was paralled neither by a reduction in CaMKII autophosphorylation, oxidation, and substrate binding nor a change in the phosphorylation of CaMKII downstream target proteins (n\u226511). The lack of CaMKII modulation by \u03b2-AR blocker treatment was confirmed in healthy wild-type mice receiving metoprolol.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\u2014<\/jats:title>\n                    <jats:p>Chronic \u03b2-AR blocker therapy in patients and in a mouse model of CaMKII-induced HF is not associated with a change in CaMKII activity. Thus, our data suggest that the molecular effects of \u03b2-AR blockers are not based on a modulation of CaMKII. Directly targeting CaMKII may, therefore, further improve HF therapy in addition to \u03b2-AR blockade.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circheartfailure.117.003840","type":"journal-article","created":{"date-parts":[[2017,5,9]],"date-time":"2017-05-09T21:00:40Z","timestamp":1494363640000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":39,"title":["Calcium\/Calmodulin-Dependent Protein Kinase II Activity Persists During Chronic \u03b2-Adrenoceptor Blockade in Experimental and Human Heart Failure"],"prefix":"10.1161","volume":"10","author":[{"given":"Matthias","family":"Dewenter","sequence":"first","affiliation":[{"name":"From the Institute of Pharmacology (M.D., C.B., L.C.Z.) and Department of Cardiology and Pneumology (S.S.), University Medical Center G\u00f6ttingen (UMG) Heart Center, Georg August University Medical School G\u00f6ttingen, Germany; Department Molecular Cardiology and Epigenetics, Heidelberg University, Germany (M.D., S.K., A.v.d.L., J.B.); DZHK (German Centre for Cardiovascular Research), Partner Sites Heidelberg\/Mannheim and G\u00f6ttingen, Germany (M.D., C.V., C.B., L.C.Z., S.K., A.v.d.L., T.W., S.S., J.B.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Neef","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology (M.D., C.B., L.C.Z.) and Department of Cardiology and Pneumology (S.S.), University Medical Center G\u00f6ttingen (UMG) Heart Center, Georg August University Medical School G\u00f6ttingen, Germany; Department Molecular Cardiology and Epigenetics, Heidelberg University, Germany (M.D., S.K., A.v.d.L., J.B.); DZHK (German Centre for Cardiovascular Research), Partner Sites Heidelberg\/Mannheim and G\u00f6ttingen, Germany (M.D., C.V., C.B., L.C.Z., S.K., A.v.d.L., T.W., S.S., J.B.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane","family":"Vettel","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology (M.D., C.B., L.C.Z.) and Department of Cardiology and Pneumology (S.S.), University Medical Center G\u00f6ttingen (UMG) Heart Center, Georg August University Medical School G\u00f6ttingen, Germany; Department Molecular Cardiology and Epigenetics, Heidelberg University, Germany (M.D., S.K., A.v.d.L., J.B.); DZHK (German Centre for Cardiovascular Research), Partner Sites Heidelberg\/Mannheim and G\u00f6ttingen, Germany (M.D., C.V., C.B., L.C.Z., S.K., A.v.d.L., T.W., S.S., J.B.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"L\u00e4mmle","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology (M.D., C.B., L.C.Z.) and Department of Cardiology and Pneumology (S.S.), University Medical Center G\u00f6ttingen (UMG) Heart Center, Georg August University Medical School G\u00f6ttingen, Germany; Department Molecular Cardiology and Epigenetics, Heidelberg University, Germany (M.D., S.K., A.v.d.L., J.B.); DZHK (German Centre for Cardiovascular Research), Partner Sites Heidelberg\/Mannheim and G\u00f6ttingen, Germany (M.D., C.V., C.B., L.C.Z., S.K., A.v.d.L., T.W., S.S., J.B.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Beushausen","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology (M.D., C.B., L.C.Z.) and Department of Cardiology and Pneumology (S.S.), University Medical Center G\u00f6ttingen (UMG) Heart Center, Georg August University Medical School G\u00f6ttingen, Germany; Department Molecular Cardiology and Epigenetics, Heidelberg University, Germany (M.D., S.K., A.v.d.L., J.B.); DZHK (German Centre for Cardiovascular Research), Partner Sites Heidelberg\/Mannheim and G\u00f6ttingen, Germany (M.D., C.V., C.B., L.C.Z., S.K., A.v.d.L., T.W., S.S., J.B.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura C.","family":"Zelarayan","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology (M.D., C.B., L.C.Z.) and Department of Cardiology and Pneumology (S.S.), University Medical Center G\u00f6ttingen (UMG) Heart Center, Georg August University Medical School G\u00f6ttingen, Germany; Department Molecular Cardiology and Epigenetics, Heidelberg University, Germany (M.D., S.K., A.v.d.L., J.B.); DZHK (German Centre for Cardiovascular Research), Partner Sites Heidelberg\/Mannheim and G\u00f6ttingen, Germany (M.D., C.V., C.B., L.C.Z., S.K., A.v.d.L., T.W., S.S., J.B.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Katz","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology (M.D., C.B., L.C.Z.) and Department of Cardiology and Pneumology (S.S.), University Medical Center G\u00f6ttingen (UMG) Heart Center, Georg August University Medical School G\u00f6ttingen, Germany; Department Molecular Cardiology and Epigenetics, Heidelberg University, Germany (M.D., S.K., A.v.d.L., J.B.); DZHK (German Centre for Cardiovascular Research), Partner Sites Heidelberg\/Mannheim and G\u00f6ttingen, Germany (M.D., C.V., C.B., L.C.Z., S.K., A.v.d.L., T.W., S.S., J.B.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"von der Lieth","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology (M.D., C.B., L.C.Z.) and Department of Cardiology and Pneumology (S.S.), University Medical Center G\u00f6ttingen (UMG) Heart Center, Georg August University Medical School G\u00f6ttingen, Germany; Department Molecular Cardiology and Epigenetics, Heidelberg University, Germany (M.D., S.K., A.v.d.L., J.B.); DZHK (German Centre for Cardiovascular Research), Partner Sites Heidelberg\/Mannheim and G\u00f6ttingen, Germany (M.D., C.V., C.B., L.C.Z., S.K., A.v.d.L., T.W., S.S., J.B.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Meyer-Roxlau","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology (M.D., C.B., L.C.Z.) and Department of Cardiology and Pneumology (S.S.), University Medical Center G\u00f6ttingen (UMG) Heart Center, Georg August University Medical School G\u00f6ttingen, Germany; Department Molecular Cardiology and Epigenetics, Heidelberg University, Germany (M.D., S.K., A.v.d.L., J.B.); DZHK (German Centre for Cardiovascular Research), Partner Sites Heidelberg\/Mannheim and G\u00f6ttingen, Germany (M.D., C.V., C.B., L.C.Z., S.K., A.v.d.L., T.W., S.S., J.B.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvio","family":"Weber","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology (M.D., C.B., L.C.Z.) and Department of Cardiology and Pneumology (S.S.), University Medical Center G\u00f6ttingen (UMG) Heart Center, Georg August University Medical School G\u00f6ttingen, Germany; Department Molecular Cardiology and Epigenetics, Heidelberg University, Germany (M.D., S.K., A.v.d.L., J.B.); DZHK (German Centre for Cardiovascular Research), Partner Sites Heidelberg\/Mannheim and G\u00f6ttingen, Germany (M.D., C.V., C.B., L.C.Z., S.K., A.v.d.L., T.W., S.S., J.B.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Wieland","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology (M.D., C.B., L.C.Z.) and Department of Cardiology and Pneumology (S.S.), University Medical Center G\u00f6ttingen (UMG) Heart Center, Georg August University Medical School G\u00f6ttingen, Germany; Department Molecular Cardiology and Epigenetics, Heidelberg University, Germany (M.D., S.K., A.v.d.L., J.B.); DZHK (German Centre for Cardiovascular Research), Partner Sites Heidelberg\/Mannheim and G\u00f6ttingen, Germany (M.D., C.V., C.B., L.C.Z., S.K., A.v.d.L., T.W., S.S., J.B.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Sossalla","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology (M.D., C.B., L.C.Z.) and Department of Cardiology and Pneumology (S.S.), University Medical Center G\u00f6ttingen (UMG) Heart Center, Georg August University Medical School G\u00f6ttingen, Germany; Department Molecular Cardiology and Epigenetics, Heidelberg University, Germany (M.D., S.K., A.v.d.L., J.B.); DZHK (German Centre for Cardiovascular Research), Partner Sites Heidelberg\/Mannheim and G\u00f6ttingen, Germany (M.D., C.V., C.B., L.C.Z., S.K., A.v.d.L., T.W., S.S., J.B.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Backs","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology (M.D., C.B., L.C.Z.) and Department of Cardiology and Pneumology (S.S.), University Medical Center G\u00f6ttingen (UMG) Heart Center, Georg August University Medical School G\u00f6ttingen, Germany; Department Molecular Cardiology and Epigenetics, Heidelberg University, Germany (M.D., S.K., A.v.d.L., J.B.); DZHK (German Centre for Cardiovascular Research), Partner Sites Heidelberg\/Mannheim and G\u00f6ttingen, Germany (M.D., C.V., C.B., L.C.Z., S.K., A.v.d.L., T.W., S.S., J.B.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan H.","family":"Brown","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology (M.D., C.B., L.C.Z.) and Department of Cardiology and Pneumology (S.S.), University Medical Center G\u00f6ttingen (UMG) Heart Center, Georg August University Medical School G\u00f6ttingen, Germany; Department Molecular Cardiology and Epigenetics, Heidelberg University, Germany (M.D., S.K., A.v.d.L., J.B.); DZHK (German Centre for Cardiovascular Research), Partner Sites Heidelberg\/Mannheim and G\u00f6ttingen, Germany (M.D., C.V., C.B., L.C.Z., S.K., A.v.d.L., T.W., S.S., J.B.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars S.","family":"Maier","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology (M.D., C.B., L.C.Z.) and Department of Cardiology and Pneumology (S.S.), University Medical Center G\u00f6ttingen (UMG) Heart Center, Georg August University Medical School G\u00f6ttingen, Germany; Department Molecular Cardiology and Epigenetics, Heidelberg University, Germany (M.D., S.K., A.v.d.L., J.B.); DZHK (German Centre for Cardiovascular Research), Partner Sites Heidelberg\/Mannheim and G\u00f6ttingen, Germany (M.D., C.V., C.B., L.C.Z., S.K., A.v.d.L., T.W., S.S., J.B.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"El-Armouche","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology (M.D., C.B., L.C.Z.) and Department of Cardiology and Pneumology (S.S.), University Medical Center G\u00f6ttingen (UMG) Heart Center, Georg August University Medical School G\u00f6ttingen, Germany; Department Molecular Cardiology and Epigenetics, Heidelberg University, Germany (M.D., S.K., A.v.d.L., J.B.); DZHK (German Centre for Cardiovascular Research), Partner Sites Heidelberg\/Mannheim and G\u00f6ttingen, Germany (M.D., C.V., C.B., L.C.Z., S.K., A.v.d.L., T.W., S.S., J.B.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10741-008-9132-8"},{"key":"e_1_3_3_3_2","first-page":"1988","article-title":"Effect of metoprolol CR\/XL in chronic heart failure: Metoprolol CR\/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).","volume":"353","author":"MERIT-HF-Study","year":"1999","unstructured":"MERIT-HF-Study. Effect of metoprolol CR\/XL in chronic heart failure: Metoprolol CR\/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:1988\u20131989.","journal-title":"Lancet"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2015.00178"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2009.10.016"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2011.01.012"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.243956"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.112.124990"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2012.11.003"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000069685.20258.F1"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000069686.31472.C5"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.109.865279"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0813013106"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1215"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2015.06.007"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI38022"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI16326"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/22.7.447"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2013.04.008"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0808393105"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201101043"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi701755q"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.006185"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00504.2009"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurjhf\/hfq129"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.091102398"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006610"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000068316.53218.49"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2010.08.639"}],"container-title":["Circulation: Heart Failure"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCHEARTFAILURE.117.003840","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T21:33:48Z","timestamp":1715549628000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCHEARTFAILURE.117.003840"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5]]},"references-count":28,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2017,5]]}},"alternative-id":["10.1161\/CIRCHEARTFAILURE.117.003840"],"URL":"https:\/\/doi.org\/10.1161\/circheartfailure.117.003840","relation":{},"ISSN":["1941-3289","1941-3297"],"issn-type":[{"value":"1941-3289","type":"print"},{"value":"1941-3297","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,5]]},"assertion":[{"value":"2016-05-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-04-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-05-09","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}