Ca2+/calmodulin-dependent kinase II triggers cell membrane injury by inducing complement factor B gene expression in the mouse heart
Ca2+/calmodulin-dependent kinase II triggers cell membrane injury by inducing complement factor B gene expression in the mouse heart
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DOI：
10.1172/jci35814
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发表时间：
2009-04-01
影响因子：
15.9
通讯作者：
Anderson, Mark E.
中科院分区：
文献类型：
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作者：
Singh, Madhu V.;Kapoun, Ann;Anderson, Mark E.
心肌Ca 2 +/钙调素依赖性蛋白激酶II（CaMKII）抑制可改善心肌梗死（MI）后的心功能，但参与心肌应激反应的CaMKII依赖性途径尚不完全清楚。为了解决这个问题，我们试图确定心肌梗死后心肌CaMKII抑制的转录后果。我们进行了基因表达谱在小鼠心脏与心肌细胞界定的转基因表达的CaMKII抑制肽（AC 3-I）或乱序控制肽（AC 3-C）后MI。在检测的8,600种mRNA中，156种受到MI的显著调节，其中近一半显示出对MI的反应与CaMK II抑制显著改变。CaMKII抑制实质上减少了MI触发的促炎基因群的上调。我们研究了这些促炎基因之一，补体因子B（Cfb），详细，因为补体蛋白分泌的细胞以外的心肌细胞可以诱导心肌梗死期间的肌膜损伤。心肌梗死和暴露于细菌内毒素期间，心肌细胞中CF B蛋白表达由NF-κ B通路的CaMK II激活触发。CaMK Ⅱ抑制抑制NF-κ B活性在体外和体内，并减少Cfb表达和肌膜损伤。Cfb（-/-）小鼠部分免受MI的不良后果。我们的研究结果表明，我们认为CaMKII是心肌损伤中CaMKII的一个新靶点，并表明CaMKII对于心肌细胞MI的遗传效应具有广泛的重要性。
Myocardial Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibition improves cardiac function following myocardial infarction (MI), but the CaMKII-dependent pathways that participate in myocardial stress responses are incompletely understood. To address this issue, we sought to determine the transcriptional consequences of myocardial CaMKII inhibition after MI. We performed gene expression profiling in mouse hearts with cardiomyocyte-delimited transgenic expression of either a CaMKII inhibitory peptide (AC3-I) or a scrambled control peptide (AC3-C) following MI. Of the 8,600 mRNAs examined, 156 were substantially modulated by MI, and nearly half of these showed markedly altered responses to MI with CaMKII inhibition. CaMKII inhibition substantially reduced the MI-triggered upregulation of a constellation of proinflammatory genes. We studied 1 of these proinflammatory genes, complement factor B (Cfb), in detail, because complement proteins secreted by cells other than cardiomyocytes can induce sarcolemmal injury during MI. CFB protein expression in cardiomyocytes was triggered by CaMKII activation of the NF-kappa B pathway during both MI and exposure to bacterial endotoxin. CaMKII inhibition suppressed NF-kappa B activity in vitro and in vivo and reduced Cfb expression and sarcolemmal injury. The Cfb(-/-) mice were partially protected from the adverse consequences of MI. Our findings demonstrate what we believe is a novel target for CaMKII in myocardial injury and suggest that CaMKII is broadly important for the genetic effects of MI in cardiomyocytes.