cAMP 诱导 HL-1 心肌细胞肥大并改变 DNA 甲基化。,American Journal of Physiology-Cell Physiology

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cAMP 诱导 HL-1 心肌细胞肥大并改变 DNA 甲基化。
American Journal of Physiology-Cell Physiology ( IF 5.0 ) Pub Date : 2015-07-29 , DOI: 10.1152/ajpcell.00058.2015
Xiefan Fang ₁ , Jourdon Robinson ₂ , John Wang-Hu ₂ , Lingli Jiang ₂ , Daniel A Freeman ₂ , Scott A Rivkees ₂ , Christopher C Wendler ₂

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cAMP 是一种高度调控的第二信使，参与许多生物过程。儿茶酚胺慢性激活 cAMP 通路会导致心脏肥大和纤维化；然而，cAMP 升高导致心肌病的机制尚不完全清楚。为了解决这个问题，我们使用稳定的 cAMP 类似物 N(6),2'-O-二丁酰腺苷 3',5'-环单磷酸增加了 HL-1 心肌细胞（一种来自成年小鼠心房的细胞系）的细胞内 cAMP 水平（DBcAMP）或磷酸二酯酶（PDE）抑制剂咖啡因和茶碱。cAMP 水平升高会增加细胞大小，并改变与肥厚型心肌病 (HCM) 相关的心脏基因和 micro-RNA 的表达水平，包括 Myh6、Myh7、Myh7b、Tnni3、Anp、Bnp、Gata4、Mef2c、Mef2d、Nfatc1、miR208a 和 miR208b 。此外，DBcAMP 改变 DNA 甲基转移酶 (Dnmts) 和 Tet 甲基胞嘧啶双加氧酶 (Tets) 的表达，这些酶调节基因组 DNA 甲基化水平。cAMP 升高诱导的 DNA 甲基化基因表达变化导致 HL-1 细胞中整体 DNA 甲基化增加。相比之下，用 5-氮杂胞苷处理抑制 DNMT 活性可降低整体 DNA 甲基化水平，并阻止 DBcAMP 处理观察到的几个 HCM 基因（Myh7、Gata4、Mef2c、Nfatc1、Myh7b、Tnni3 和 Bnp）表达的增加。这些结果表明，cAMP 在体外诱导心肌细胞肥大并改变 HCM 基因表达，并且 DNA 甲基化模式介导 cAMP 诱导的 HCM 基因上调。

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cAMP induces hypertrophy and alters DNA methylation in HL-1 cardiomyocytes.

cAMP is a highly regulated secondary messenger involved in many biological processes. Chronic activation of the cAMP pathway by catecholamines results in cardiac hypertrophy and fibrosis; however, the mechanism by which elevated cAMP leads to cardiomyopathy is not fully understood. To address this issue, we increased intracellular cAMP levels in HL-1 cardiomyocytes, a cell line derived from adult mouse atrium, using either the stable cAMP analog N(6),2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (DBcAMP) or phosphodiesterase (PDE) inhibitors caffeine and theophylline. Elevated cAMP levels increased cell size and altered expression levels of cardiac genes and micro-RNAs associated with hypertrophic cardiomyopathy (HCM), including Myh6, Myh7, Myh7b, Tnni3, Anp, Bnp, Gata4, Mef2c, Mef2d, Nfatc1, miR208a, and miR208b. In addition, DBcAMP altered the expression of DNA methyltransferases (Dnmts) and Tet methylcytosine dioxygenases (Tets), enzymes that regulate genomic DNA methylation levels. Changes in expression of DNA methylation genes induced by elevated cAMP led to increased global DNA methylation in HL-1 cells. In contrast, inhibition of DNMT activity with 5-azacytidine treatment decreased global DNA methylation levels and blocked the increased expression of several HCM genes (Myh7, Gata4, Mef2c, Nfatc1, Myh7b, Tnni3, and Bnp) observed with DBcAMP treatment. These results demonstrate that cAMP induces cardiomyocyte hypertrophy and altered HCM gene expression in vitro and that DNA methylation patterns mediate the upregulation of HCM genes induced by cAMP. These data identify a previously unknown mechanism by which elevated levels of cAMP lead to increased expression of genes associated with cardiomyocyte hypertrophy.

更新日期：2019-11-01

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