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Inhibition of Elevated Ca2+/Calmodulin-Dependent Protein Kinase II Improves Contractility in Human Failing Myocardium
Open accessAbstract
Rationale: Heart failure (HF) is known to be associated with increased Ca 2+/calmodulin-dependent protein kinase (CaMK)II expression and activity. There is still controversial discussion about the functional role of CaMKII in HF. Moreover, CaMKII inhibition has never been investigated in human myocardium. Objective: We sought to investigate detailed CaMKIIδ expression in end-stage failing human hearts (dilated and ischemic cardiomyopathy) and the functional effects of CaMKII inhibition on contractility. Methods and Results: Expression analysis revealed that CaMKIIδ, both cytosolic δ C and nuclear δ B splice variants, were significantly increased in both right and left ventricles from patients with dilated or ischemic cardiomyopathy versus nonfailing. Experiments with isometrically twitching trabeculae revealed significantly improved force frequency relationships in the presence of CaMKII inhibitors (KN-93 and AIP). Increased postrest twitches after CaMKII inhibition indicated an improved sarcoplasmic reticulum (SR) Ca 2+loading. This was confirmed in isolated myocytes by a reduced SR Ca 2+spark frequency and hence SR Ca 2+leak, resulting in increased SR Ca 2+load when inhibiting CaMKII. Ryanodine receptor type 2 phosphorylation at Ser2815, which is known to be phosphorylated by CaMKII thereby contributing to SR Ca 2+leak, was found to be markedly reduced in KN-93–treated trabeculae. Interestingly, CaMKII inhibition did not influence contractility in nonfailing sheep trabeculae. Conclusions: The present study shows for the first time that CaMKII inhibition acutely improves contractility in human HF where CaMKIIδ expression is increased. The mechanism proposed consists of a reduced SR Ca 2+leak and consequently increased SR Ca 2+load. Thus, CaMKII inhibition appears to be a possible therapeutic option for patients with HF and merits further investigation.
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“Note that the trabeculae from Sossalla et al. 2010 were in presence of KN-92, an inactive analogue of the CaMKII inhibitor KN-93.”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Sossalla, et al., 2010
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“Increasing stimulation frequency in sheep trabeculae from 0.5 Hz to 2 Hz resulted in a 139–171% increase in force production (Schotola, et al., 2011; Sossalla, et al., 2010).”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Sossalla, et al., 2010
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Metadata
- Authors
- Sossalla, S., Fluschnik, N., Schotola, H., Ort, K. R., Neef, S., Schulte, T., Wittköpper, K., Renner, A., Schmitto, J. D., Gummert, J., El-Armouche, A., Hasenfuss, G., & Maier, L. S.
- Affiliations
- Brigham and Women's Hospital (US)
- From the Departments of Cardiology and Pneumology (S.S., N.F., K.R.O., S.N., T.S., G.H., L.S.M.), Anesthesiology (H.S.), Pharmacology (K.W., A.E.-A.), Georg-August-University Göttingen, Germany; Department of Cardiovascular Surgery (A.R., J.G.), Heart and Diabetes Center, Bad Oeynhausen, Germany; and Division of Cardiac Surgery (J.D.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
- ORCID
- Venue
- Circulation Research
- Published
- 2010-10-29
- Volume
- 107
- Issue
- 9
- Pages
- 1150-1161
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2159995809
- Cited by
- 237
- References
- 35
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 7 · 2023: 7 · 2022: 11 · 2021: 15 · 2020: 18 · 2019: 9 · 2018: 17 · 2017: 13 · 2016: 18 · 2015: 16 · 2014: 17 · 2013: 21 · 2012: 25
- FWCI
- 16.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- GRO (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- CaMKII, heart failure, cardiomyocyte contractility, dilated cardiomyopathy, ischemic cardiomyopathy, sarcoplasmic reticulum Ca2+ leak, ryanodine receptor phosphorylation, KN-93, AIP, force-frequency relationship
- MeSH terms
- Animals, Cells, Cultured, Heart Failure, Humans, Myocardial Contraction, Myocardium, Sheep, Protein Kinase Inhibitors, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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