Biomaterial Database

Calcium/Calmodulin-Dependent Protein Kinase II Activity Persists During Chronic β-Adrenoceptor Blockade in Experimental and Human Heart Failure. 2017

Matthias Dewenter, and Stefan Neef, and Christiane Vettel, and Simon Lämmle, and Christina Beushausen, and Laura C Zelarayan, and Sylvia Katz, and Albert von der Lieth, and Stefanie Meyer-Roxlau, and Silvio Weber, and Thomas Wieland, and Samuel Sossalla, and Johannes Backs, and Joan H Brown, and Lars S Maier, and Ali El-Armouche

From the Institute of Pharmacology (M.D., C.B., L.C.Z.) and Department of Cardiology and Pneumology (S.S.), University Medical Center Göttingen (UMG) Heart Center, Georg August University Medical School Göttingen, 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 Göttingen, Germany (M.D., C.V., C.B., L.C.Z., S.K., A.v.d.L., T.W., S.S., J.B.); Department of Internal Medicine II, University Hospital Regensburg, Germany (S.N., S.S., L.S.M.); Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Germany (C.V., T.W.); Institute of Pharmacology and Toxicology, University of Technology Dresden, Germany (S.L., S.M.-R., S.W., A.E.-A.); and Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla (J.H.B.).

BACKGROUND 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 β-adrenoceptor (β-AR) stimulation. Recent studies indicate a significant cross talk 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. 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 with 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, CaMKIIδC transgenic mice were treated with the β1-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% premature ventricular contractions; P<0.05). On a molecular level, metoprolol expectedly decreased protein kinase A-dependent phospholamban and ryanodine receptor 2 phosphorylation (-42±9% for P-phospholamban-S16 and -22±7% for P-ryanodine receptor 2-S2808; P<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≥11). The lack of CaMKII modulation by β-AR blocker treatment was confirmed in healthy wild-type 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 suggest 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.

UI	MeSH Term	Description	Entries
D008790	Metoprolol	A selective adrenergic beta-1 blocking agent that is commonly used to treat ANGINA PECTORIS; HYPERTENSION; and CARDIAC ARRHYTHMIAS.	Beloc-Duriles,Betaloc,Betaloc-Astra,Betalok,CGP-2175,H 93-26,Lopressor,Metoprolol CR-XL,Metoprolol Succinate,Metoprolol Tartrate,Seloken,Spesicor,Spesikor,Toprol,Toprol-XL,Beloc Duriles,Betaloc Astra,CGP 2175,CGP2175,H 93 26,H 9326,Metoprolol CR XL,Toprol XL
D008822	Mice, Transgenic	Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN.	Transgenic Mice,Founder Mice, Transgenic,Mouse, Founder, Transgenic,Mouse, Transgenic,Mice, Transgenic Founder,Transgenic Founder Mice,Transgenic Mouse
D004195	Disease Models, Animal	Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases.	Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004452	Echocardiography	Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic.	Echocardiography, Contrast,Echocardiography, Cross-Sectional,Echocardiography, M-Mode,Echocardiography, Transthoracic,Echocardiography, Two-Dimensional,Transthoracic Echocardiography,2-D Echocardiography,2D Echocardiography,Contrast Echocardiography,Cross-Sectional Echocardiography,Echocardiography, 2-D,Echocardiography, 2D,M-Mode Echocardiography,Two-Dimensional Echocardiography,2 D Echocardiography,Cross Sectional Echocardiography,Echocardiography, 2 D,Echocardiography, Cross Sectional,Echocardiography, M Mode,Echocardiography, Two Dimensional,M Mode Echocardiography,Two Dimensional Echocardiography
D006333	Heart Failure	A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (VENTRICULAR DYSFUNCTION), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as MYOCARDIAL INFARCTION.	Cardiac Failure,Heart Decompensation,Congestive Heart Failure,Heart Failure, Congestive,Heart Failure, Left-Sided,Heart Failure, Right-Sided,Left-Sided Heart Failure,Myocardial Failure,Right-Sided Heart Failure,Decompensation, Heart,Heart Failure, Left Sided,Heart Failure, Right Sided,Left Sided Heart Failure,Right Sided Heart Failure
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000319	Adrenergic beta-Antagonists	Drugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety.	Adrenergic beta-Antagonist,Adrenergic beta-Receptor Blockader,Adrenergic beta-Receptor Blockaders,beta-Adrenergic Antagonist,beta-Adrenergic Blocker,beta-Adrenergic Blocking Agent,beta-Adrenergic Blocking Agents,beta-Adrenergic Receptor Blockader,beta-Adrenergic Receptor Blockaders,beta-Adrenoceptor Antagonist,beta-Blockers, Adrenergic,beta-Adrenergic Antagonists,beta-Adrenergic Blockers,beta-Adrenoceptor Antagonists,Adrenergic beta Antagonist,Adrenergic beta Antagonists,Adrenergic beta Receptor Blockader,Adrenergic beta Receptor Blockaders,Adrenergic beta-Blockers,Agent, beta-Adrenergic Blocking,Agents, beta-Adrenergic Blocking,Antagonist, beta-Adrenergic,Antagonist, beta-Adrenoceptor,Antagonists, beta-Adrenergic,Antagonists, beta-Adrenoceptor,Blockader, Adrenergic beta-Receptor,Blockader, beta-Adrenergic Receptor,Blockaders, Adrenergic beta-Receptor,Blockaders, beta-Adrenergic Receptor,Blocker, beta-Adrenergic,Blockers, beta-Adrenergic,Blocking Agent, beta-Adrenergic,Blocking Agents, beta-Adrenergic,Receptor Blockader, beta-Adrenergic,Receptor Blockaders, beta-Adrenergic,beta Adrenergic Antagonist,beta Adrenergic Antagonists,beta Adrenergic Blocker,beta Adrenergic Blockers,beta Adrenergic Blocking Agent,beta Adrenergic Blocking Agents,beta Adrenergic Receptor Blockader,beta Adrenergic Receptor Blockaders,beta Adrenoceptor Antagonist,beta Adrenoceptor Antagonists,beta Blockers, Adrenergic,beta-Antagonist, Adrenergic,beta-Antagonists, Adrenergic,beta-Receptor Blockader, Adrenergic,beta-Receptor Blockaders, Adrenergic
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D015151	Immunoblotting	Immunologic method used for detecting or quantifying immunoreactive substances. The substance is identified by first immobilizing it by blotting onto a membrane and then tagging it with labeled antibodies.	Dot Immunoblotting,Electroimmunoblotting,Immunoelectroblotting,Reverse Immunoblotting,Immunoblotting, Dot,Immunoblotting, Reverse,Dot Immunoblottings,Electroimmunoblottings,Immunoblottings,Immunoblottings, Dot,Immunoblottings, Reverse,Immunoelectroblottings,Reverse Immunoblottings
D051379	Mice	The common name for the genus Mus.	Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus