While systolic cardiomyocyte function is preserved, diastolic myocyte function and recovery from acidosis are impaired in CaMKIIδ-KO mice.
While systolic cardiomyocyte function is preserved, diastolic myocyte function and recovery from acidosis are impaired in CaMKIIδ-KO mice.
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DOI：
10.1016/j.yjmcc.2013.02.014
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发表时间：
2013-06
影响因子：
5
通讯作者：
Maier, Lars S.
中科院分区：
文献类型：
--
作者：
Neef, Stefan;Sag, Can M.;Daut, Maria;Baeumer, Henrik;Grefe, Clemens;El-Armouche, Ali;DeSantiago, Jaime;Pereira, Laetitia;Bers, Donald M.;Backs, Johannes;Maier, Lars S.
CaMKII通过诱导SR Ca 2 +-泄漏而导致心力衰竭中收缩力受损。心脏中的CaMKII抑制被认为是一种新的治疗原则。存在不同的CaMKII同种型。特异性靶向CaMKIIδ（心脏中的主要亚型）可能具有治疗潜力，而不会损害其他CaMKII亚型。我们研究了在基础条件下和应激时，即在β-肾上腺素能刺激和酸中毒期间，心肌细胞功能是否受到CaMKIIδ同种型特异性敲除（KO）的影响。在KO体内（超声心动图），对应于不变的Ca 2+瞬时振幅和体外分离的肌细胞收缩性，在很大程度上保留了心功能。CaMKII活性显著降低，而磷酸酶-1抑制剂-1显著增加。令人惊讶的是，虽然KO中舒张期Ca 2+消除较慢，最有可能是由于受磷蛋白Thr-17磷酸化减少，但仍然存在频率依赖性舒张加速。尽管在较低频率下SR Ca 2+再摄取减少，但SR Ca 2+含量并未减少，这可能是由于较低的RyR Ser-2815磷酸化导致KO中舒张期SR Ca 2+损失减少。用异丙肾上腺素处理KO心肌细胞显示出完整的变力性和负性反应。在酸中毒期间，KO中SR Ca 2+再吸收和SR Ca 2+负载显着受损，导致酸中毒期间无法维持收缩期Ca 2+瞬变并损害恢复。在基础生理条件下，抑制CaMKIIδ似乎是安全的。存在特定条件（例如在酸中毒期间），在该条件下，CaMKII抑制可能没有帮助甚至有害。这些条件将必须更清楚地定义之前，CaMKII抑制剂用于治疗。
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. 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. 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. 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.
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影响因子：
37.8
作者：
Toischer K;Rokita AG;Unsöld B;Zhu W;Kararigas G;Sossalla S;Reuter SP;Becker A;Teucher N;Seidler T;Grebe C;Preuss L;Gupta SN;Schmidt K;Lehnart SE;Krüger M;Linke WA;Backs J;Regitz-Zagrosek V;Schäfer K;Field LJ;Maier LS;Hasenfuss G
通讯作者：
Hasenfuss G
影响因子：
56.9
作者：
De Koninck, P;Schulman, H
通讯作者：
Schulman, H
影响因子：
5.5
作者：
Ronkainen, Jarkko J.;Hanninen, Sandra L.;Tavi, Pasi
通讯作者：
Tavi, Pasi
DOI：
10.1016/j.ddmec.2010.07.005
发表时间：
2010-01-01
期刊：
Drug discovery today. Disease mechanisms
影响因子：
--
作者：
Schulman, Howard;Anderson, Mark E
通讯作者：
Anderson, Mark E
影响因子：
5
作者：
DeSantiago, J;Maier, LS;Bers, DM
通讯作者：
Bers, DM