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      CaMKII Activity Persists During Chronic β-Adrenoceptor Blockade in Experimental and Human Heart Failure

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          Abstract

          Background

          Considerable evidence suggests that CaMKII overactivity plays a crucial role in the pathophysiology of heart failure (HF), a condition characterized by excessive β-adrenoceptor (β-AR) stimulation. Recent studies indicate a significant crosstalk between β-AR signaling and CaMKII activation presenting CaMKII as a possible downstream mediator of detrimental β-AR signaling in HF. In this study we investigated the effect of chronic β-AR blocker treatment on CaMKII activity in human and experimental HF.

          Methods and Results

          Immunoblot analysis of myocardium from end stage HF patients (n=12) and non-HF subjects undergoing cardiac surgery (n=12) treated with β-AR blockers revealed no difference in CaMKII activity when compared to non-β-AR-blocker-treated 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, CaMKIIδ C transgenic mice were treated with the β 1-AR blocker metoprolol (270 mg/kg*d). Metoprolol significantly reduced transgene-associated mortality (n≥29, p<0.001), attenuated the development of cardiac hypertrophy (−14±6% heart weight/tibia length, p<0.05) and strongly reduced ventricular arrhythmias (−70±22% PVCs, p<0.05). On a molecular level, metoprolol expectedly decreased PKA dependent phospholamban (PLN) and ryanodine receptor 2 (RyR2) phosphorylation (−42±9% for P-PLN-S16 and −22±7% for P-RyR2-S2808, p<0.05). However, this was neither paralleled by a reduction in CaMKII autophosphorylation, oxidation and substrate binding nor a change in the phosphorylation of CaMKII downstream target proteins (n≥11). The lack of CaMKII modulation by β-AR blocker treatment was confirmed in healthy wildtype mice receiving metoprolol.

          Conclusions

          Chronic β-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 suggests that the molecular effects of β-AR blockers are not based on a modulation of CaMKII. Directly targeting CaMKII may therefore further improve HF therapy in addition to β-AR blockade.

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          Author and article information

          Journal
          101479941
          35681
          Circ Heart Fail
          Circ Heart Fail
          Circulation. Heart failure
          1941-3289
          1941-3297
          18 April 2017
          May 2017
          01 May 2018
          : 10
          : 5
          : e003840
          Affiliations
          [1 ]Institute of Pharmacology, University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, Germany
          [2 ]Department Molecular Cardiology and Epigenetics, Heidelberg University, Germany
          [3 ]DZHK (German Centre for Cardiovascular Research), Partner Sites Heidelberg/Mannheim and Göttingen, Germany
          [4 ]Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
          [5 ]Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Germany
          [6 ]Institute of Pharmacology and Toxicology, University of Technology Dresden, Germany
          [7 ]Department of Cardiology and Pneumology, UMG Heart Center, Georg August University Medical School Göttingen, Germany
          [8 ]Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, US
          Author notes
          Corresponding author: Ali El-Armouche, MD, Institute of Pharmacology and Toxicology, University of Technology Dresden, Fetscherstr. 74, 01307 Dresden, Germany., Phone: 49-351-458-6300; Fax: 49-351-458-6315; ali.el-armouche@ 123456tu-dresden.de
          [§]

          M.D. and A.E.-A. contributed equally.

          Article
          PMC5479434 PMC5479434 5479434 nihpa868398
          10.1161/CIRCHEARTFAILURE.117.003840
          5479434
          28487342
          83706039-4864-42c9-a142-7dd3a736af1a
          History
          Categories
          Article

          beta-adrenergic receptor blocker,heart failure,calcium/calmodulin-dependent protein kinase II,Heart Failure,Animal Models of Human Disease,Pharmacology,Mechanisms

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