Targeting the CaMKII/ERK Interaction in the Heart Prevents Cardiac Hypertrophy.
Targeting the CaMKII/ERK Interaction in the Heart Prevents Cardiac Hypertrophy.
复制标题
靶向心脏中的CAMKII/ERK相互作用可防止心脏肥大。
DOI：
10.1371/journal.pone.0130477
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Illario M
中科院分区：
文献类型：
--
作者：
Cipolletta E;Rusciano MR;Maione AS;Santulli G;Sorriento D;Del Giudice C;Ciccarelli M;Franco A;Crola C;Campiglia P;Sala M;Gomez-Monterrey I;De Luca N;Trimarco B;Iaccarino G;Illario M
Ca 2 +/钙调素蛋白激酶II（CaMKII）的激活是心肌肥大信号传导的重要步骤。CaMKII与心脏中其他通路整合的分子机制尚未完全了解。我们推测CaMK Ⅱ与细胞外调节激酶（ERK）的结合，通过ERK核定位促进心肌肥大。在H9 C2成心肌细胞中，选择性CaMKII肽抑制剂AntCaNtide、其穿膜肽缀合的最小抑制序列类似物tat-CN 17 β和MEK/ERK抑制剂UO 126均减少苯肾上腺素（PE）介导的ERK和CaMKII活化及其相互作用。此外，AntCaNtide或tat-CN 17 β预处理可阻止PE诱导的H9 C2细胞中CaMKII和ERK核积聚，并减轻肥大反应。为了确定CaMK II在体内心脏肥大中的作用，对自发性高血压大鼠进行心肌内注射AntCaNtide或tat-CN 17 β。每周通过心脏超声评估左心室肥大，持续3周。我们观察到，用CaMK II抑制剂治疗诱导了类似但显著的心脏大小、左心室质量和心壁厚度的减小。用CaMKII抑制剂治疗引起CaMKII和ERK磷酸化水平及其在心脏中的核定位的显著降低。这些结果表明，CaMKII和ERK相互作用，以促进激活肥大;抑制CaMKII-ERK相互作用提供了一种新的治疗方法，以限制心脏肥大。
Activation of Ca2+/Calmodulin protein kinase II (CaMKII) is an important step in signaling of cardiac hypertrophy. The molecular mechanisms by which CaMKII integrates with other pathways in the heart are incompletely understood. We hypothesize that CaMKII association with extracellular regulated kinase (ERK), promotes cardiac hypertrophy through ERK nuclear localization. In H9C2 cardiomyoblasts, the selective CaMKII peptide inhibitor AntCaNtide, its penetratin conjugated minimal inhibitory sequence analog tat-CN17β, and the MEK/ERK inhibitor UO126 all reduce phenylephrine (PE)-mediated ERK and CaMKII activation and their interaction. Moreover, AntCaNtide or tat-CN17β pretreatment prevented PE induced CaMKII and ERK nuclear accumulation in H9C2s and reduced the hypertrophy responses. To determine the role of CaMKII in cardiac hypertrophy in vivo, spontaneously hypertensive rats were subjected to intramyocardial injections of AntCaNtide or tat-CN17β. Left ventricular hypertrophy was evaluated weekly for 3 weeks by cardiac ultrasounds. We observed that the treatment with CaMKII inhibitors induced similar but significant reduction of cardiac size, left ventricular mass, and thickness of cardiac wall. The treatment with CaMKII inhibitors caused a significant reduction of CaMKII and ERK phosphorylation levels and their nuclear localization in the heart. These results indicate that CaMKII and ERK interact to promote activation in hypertrophy; the inhibition of CaMKII-ERK interaction offers a novel therapeutic approach to limit cardiac hypertrophy.
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影响因子：
4.8
作者：
Kahl, CR;Means, AR
通讯作者：
Means, AR
DOI：
10.1152/ajpheart.00514.2007
发表时间：
2007-09-01
影响因子：
4.8
作者：
Banerjee, Indroneal;Fuseler, John W.;Baudino, Troy A.
通讯作者：
Baudino, Troy A.
影响因子：
4.8
作者：
HE, TC;JIANG, N;WOJCHOWSKI, DM
通讯作者：
WOJCHOWSKI, DM
影响因子：
--
作者：
Colomer, JM;Mao, L;Means, AR
通讯作者：
Means, AR
影响因子：
64.5
作者：
Erickson, Jeffrey R.;Joiner, Mei-ling A.;Anderson, Mark E.
通讯作者：
Anderson, Mark E.