The A-kinase anchor protein AKAP121 is a negative regulator of cardiomyocyte hypertrophy
The A-kinase anchor protein AKAP121 is a negative regulator of cardiomyocyte hypertrophy
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DOI：
10.1016/j.yjmcc.2009.01.018
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发表时间：
2009-05-01
影响因子：
5
通讯作者：
Czubryt, Michael P.
中科院分区：
文献类型：
--
作者：
Abrenica, Bernard;AlShaaban, Mohamed;Czubryt, Michael P.
病理性心脏肥大给患者带来了重大的临床负担，但对其诱导的精确细胞内机制仅部分了解。我们研究了AKAP 121在调节心肌细胞肥大中的潜在作用，因为最近的报道表明其他AKAP参与了这一过程。我们在这里报告，敲低AKAP 121表达在分离的新生大鼠心肌细胞的结果在显着的细胞肥大。AKAP 121表达的缺失与NFATc3的去磷酸化和核定位相关，NFATc3是肥大性磷酸酶钙调磷酸酶的下游效应物。我们还表明，AKAP121在心肌细胞中的过度表达减少了基底细胞的大小，并阻止由异丙肾上腺素诱导的肥大，表明AKAP121负调控肥大过程。免疫共沉淀数据表明AKAP 121和钙调磷酸酶直接相互作用。我们的研究结果与AKAP 121表达缺失导致钙调磷酸酶活性池释放的模型一致，进而导致NFATc3核转位和肥大基因程序激活。这些结果首次鉴定了AKAP 121作为心肌细胞肥大的负调节剂，并突出了AKAP 121作为治疗开发的潜在靶点。(C)2009 Elsevier Inc. All rights reserved.
Pathologic cardiac hypertrophy imposes a significant clinical burden on patients, yet the precise intracellular mechanisms responsible for its induction are only partially understood. We examined a potential role for AKAP121 to regulate cardiomyocyte hypertrophy, since recent reports have implicated other AKAPs in this process. We report here that knockdown of AKAP121 expression in isolated neonatal rat cardiomyocytes results in pronounced cellular hypertrophy. Loss of AKAP121 expression is associated with dephosphorylation and nuclear localization of NFATc3, a downstream effector of the hypertrophic phosphatase calcineurin. We also demonstrate that over-expression of AKAP121 in cardiac myocytes reduces basal cell size, and blocks hypertrophy induced by isoproterenol, indicating that AKAP121 negatively regulates the hypertrophic process. Co-immunoprecipitation data indicates that AKAP121 and calcineurin directly interact. Our findings are consistent with a model in which loss of AKAP121 expression leads to the release of an active pool of calcineurin, in turn causing nuclear translocation of NFATc3 and activation of the hypertrophic gene program. These results are the first to identify AKAP121 as a negative regulator Of cardiomyocyte hypertrophy, and highlight AKAP121 as a potential target for therapeutic exploitation. (C) 2009 Elsevier Inc. All rights reserved.