While systolic cardiomyocyte function is preserved, diastolic myocyte function and recovery from acidosis are impaired in CaMKIIδ-KO mice
Objective - CaMKII contributes to impaired contractility in heart failure by inducing SR Ca2+-leak. CaMKII-inhibition in the heart was suggested to be a novel therapeutic principle. Different CaMKII isoforms exist. Specifically targeting CaMKIIδ, the dominant isoform in the heart, could be of therap...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
6 March 2013
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| In: |
Journal of molecular and cellular cardiology
Year: 2013, Volume: 59, Pages: 107-116 |
| ISSN: | 1095-8584 |
| DOI: | 10.1016/j.yjmcc.2013.02.014 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.yjmcc.2013.02.014 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0022282813000795 
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| Author Notes: | Stefan Neef, Can M. Sag, Maria Daut, Henrik Bäumer, Clemens Grefe, Ali El-Armouche, Jaime DeSantiago, Laetitia Pereira, Donald M. Bers, Johannes Backs, Lars S. Maier |
MARC
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| 245 | 1 | 0 | |a While systolic cardiomyocyte function is preserved, diastolic myocyte function and recovery from acidosis are impaired in CaMKIIδ-KO mice |c Stefan Neef, Can M. Sag, Maria Daut, Henrik Bäumer, Clemens Grefe, Ali El-Armouche, Jaime DeSantiago, Laetitia Pereira, Donald M. Bers, Johannes Backs, Lars S. Maier |
| 246 | 3 | 3 | |a While systolic cardiomyocyte function is preserved, diastolic myocyte function and recovery from acidosis are impaired in CaMKIIdelta-KO mice |
| 264 | 1 | |c 6 March 2013 | |
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| 520 | |a Objective - CaMKII contributes to impaired contractility in heart failure by inducing SR Ca2+-leak. CaMKII-inhibition in the heart was suggested to be a novel therapeutic principle. Different CaMKII isoforms exist. Specifically targeting CaMKIIδ, the dominant isoform in the heart, could be of therapeutic potential without impairing other CaMKII isoforms. - Rationale - We investigated whether cardiomyocyte function is affected by isoform-specific knockout (KO) of CaMKIIδ under basal conditions and upon stress, i.e. upon ß-adrenergic stimulation and during acidosis. - Results - Systolic cardiac function was largely preserved in the KO in vivo (echocardiography) corresponding to unchanged Ca2+-transient amplitudes and isolated myocyte contractility in vitro. CaMKII activity was dramatically reduced while phosphatase-1 inhibitor-1 was significantly increased. Surprisingly, while diastolic Ca2+-elimination was slower in KO most likely due to decreased phospholamban Thr-17 phosphorylation, frequency-dependent acceleration of relaxation was still present. Despite decreased SR Ca2+-reuptake at lower frequencies, SR Ca2+-content was not diminished, which might be due to reduced diastolic SR Ca2+-loss in the KO as a consequence of lower RyR Ser-2815 phosphorylation. Challenging KO myocytes with isoproterenol showed intact inotropic and lusitropic responses. During acidosis, SR Ca2+-reuptake and SR Ca2+-loading were significantly impaired in KO, resulting in an inability to maintain systolic Ca2+-transients during acidosis and impaired recovery. - Conclusions - Inhibition of CaMKIIδ appears to be safe under basal physiologic conditions. Specific conditions exist (e.g. during acidosis) under which CaMKII-inhibition might not be helpful or even detrimental. These conditions will have to be more clearly defined before CaMKII inhibition is used therapeutically. | ||
| 650 | 4 | |a Acidosis | |
| 650 | 4 | |a Calcium handling | |
| 650 | 4 | |a CaMKII | |
| 650 | 4 | |a Excitation contraction coupling | |
| 650 | 4 | |a SERCA function | |
| 650 | 4 | |a SR Ca-leak | |
| 700 | 1 | |a Sag, Can M. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Daut, Maria |e VerfasserIn |4 aut | |
| 700 | 1 | |a Bäumer, Henrik |e VerfasserIn |4 aut | |
| 700 | 1 | |a Grefe, Clemens |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Maier, Lars S. |e VerfasserIn |4 aut | |
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