Buchumschlag

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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Bibliographische Detailangaben
Hauptverfasser: Neef, Stefan (VerfasserIn) , Sag, Can M. (VerfasserIn) , Daut, Maria (VerfasserIn) , Bäumer, Henrik (VerfasserIn) , Grefe, Clemens (VerfasserIn) , El-Armouche, Ali (VerfasserIn) , DeSantiago, Jaime (VerfasserIn) , Pereira, Laetitia (VerfasserIn) , Bers, Donald M. (VerfasserIn) , Backs, Johannes (VerfasserIn) , Maier, Lars S. (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 6 March 2013
In: Journal of molecular and cellular cardiology
Year: 2013, Jahrgang: 59, Pages: 107-116
ISSN:1095-8584
DOI:10.1016/j.yjmcc.2013.02.014
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Verfasserangaben: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
Beschreibung
Zusammenfassung: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.
Beschreibung:Gesehen am 08.12.2021
Beschreibung:Online Resource
ISSN:1095-8584
DOI:10.1016/j.yjmcc.2013.02.014

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