Neural cell adhesion molecule is a cardioprotective factor up-regulated by metabolic stress
Neural cell adhesion molecule is a cardioprotective factor up-regulated by metabolic stress
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DOI：
10.1016/j.yjmcc.2009.10.014
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发表时间：
2010-06-01
影响因子：
5
通讯作者：
Kimura, Takeshi
中科院分区：
文献类型：
--
作者：
Nagao, Kazuya;Ono, Koh;Kimura, Takeshi
筛选在应激条件下上调的细胞表面蛋白可能导致识别新的治疗靶点。以H9C2大鼠心肌成肌细胞为研究对象，采用信号序列捕捉法，寻找线粒体-F0F1-ATP合酶抑制剂寡霉素促进心肌成肌细胞表达的基因。已发现的基因之一是神经细胞黏附分子(NCAM，CD56)，它是神经系统中发育、细胞存活、迁移和轴突生长的主要调节因子。在小鼠心肌梗死模型中的免疫组织化学分析显示，NCAM在梗死区残留的心肌细胞中强烈表达。在高血压诱导的心力衰竭大鼠模型的重塑过程中，也发现NCAM的表达增加。慢病毒介导的NCAM基因敲除降低了寡霉素处理后H9C2细胞的生长和存活。在原代培养的新生大鼠心肌细胞中，NCAM也被发现上调，并在寡霉素处理后起到保护作用。下游信号分析显示，NCAM的敲除显著降低了基础AKT的磷酸化水平。相反，NCAM模拟肽P2d激活AKT并显著减少寡霉素诱导的心肌细胞死亡，这一作用可被PI3K抑制剂LY-294002和显性阴性AKT突变体的过表达所消除。这些发现表明，NCAM是一种心肌保护因子，在代谢应激下心肌细胞中上调，这一信号的增强可提高存活率。(C)2009爱思唯尔有限公司。保留所有权利。
Screening for cell surface proteins up-regulated under stress conditions may lead to the identification of new therapeutic targets. To search for genes whose expression was enhanced by treatment with oligomycin, a mitochondrial-F0F1 ATP synthase inhibitor, signal sequence trapping was performed in H9C2 rat cardiac myoblasts. One of the genes identified was that for neural cell adhesion molecule (NCAM, CD56), a major regulator of development, cell survival, migration, and neurite outgrowth in the nervous system. Immunohistochemical analyses in a mouse myocardial infarction model revealed that NCAM was strongly expressed in residual cardiac myocytes in the infarcted region. Increased expression of NCAM was also found during the remodeling period in a rat model of hypertension-induced heart failure. Lentivirus-mediated knockdown of NCAM decreased the cell growth and survival following oligomycin treatment in H9C2 cells. In primary rat neonatal cardiac myocytes, NCAM was also found to be up-regulated and played a protective role following oligomycin treatment. Analyses of downstream signaling revealed that knockdown of NCAM significantly decreased the basal AKT phosphorylation level. In contrast, NCAM mimetic peptide P2d activated AKT and significantly reduced oligomycin-induced cardiomyocyte death, which was abolished by treatment with the PI3K inhibitor LY-294002 as well as overexpression of the dominant-negative AKT mutant. These findings demonstrate that NCAM is a cardioprotective factor up-regulated under metabolic stress in cardiomyocytes and augmentation of this signal improved survival. (C) 2009 Elsevier Ltd. All rights reserved.