COX-2 is involved in ET-1-induced hypertrophy of neonatal rat cardiomyocytes: Role of NFATc3
COX-2 is involved in ET-1-induced hypertrophy of neonatal rat cardiomyocytes: Role of NFATc3
复制标题
DOI：
10.1016/j.mce.2013.11.012
复制
发表时间：
2014-02
影响因子：
4.1
通讯作者：
Hong Li;Si Gao;Jiantao Ye;Xiao-jun Feng;Yi Cai;Zhiping Liu;Jing Lu;Qin Li;Xiao-yang Huang-Xiao-yang-Hua
中科院分区：
文献类型：
--
作者：
Hong Li;Si Gao;Jiantao Ye;Xiao-jun Feng;Yi Cai;Zhiping Liu;Jing Lu;Qin Li;Xiao-yang Huang-Xiao-yang-Hua
内皮素-1(ET-1)是参与心力衰竭的重要分子。已证实ET-1刺激可导致体内外心肌肥厚，但其机制尚不清楚。在本研究中，我们报道了环氧合酶-2(COX-2)可能是ET-1刺激的肥大反应的重要介质。在培养的乳鼠心肌细胞中，ET-1显著上调COX-2的表达和活性，并伴随着细胞表面积和BNP mRNA水平的增加。COX-2选择性抑制剂NS-398和塞来昔布或COX-2 RNA干扰可消除ET-1依赖的心肌细胞肥大，但这种抑制作用可被PGE2抑制。此外，环孢素A(CsA)和抑制活化T细胞核因子c3(NFATc3)抑制了ET-1诱导的COX-2的表达，NFATc3也能与COX-2基因启动子区域的-GGAAA-序列结合，提示钙调神经磷酸酶/NFATc3信号参与了ET-1诱导的COX-2的转录调控。这些发现进一步揭示了ET-1在心肌肥厚中的作用，并提出了一种通过抑制COX-2来对抗心肌肥厚的潜在治疗策略。
Endothelin-1 (ET-1) is a critical molecule that involved in heart failure. It has been proved that ET-1 stimulation results in cardiac hypertrophy bothin vitroandin vivo, but the mechanisms underlying remain largely unknown. In this study, we reported that cyclooxygenase-2 (COX-2) might be an important mediator of hypertrophic responses to ET-1 stimulation. In the cultured rat neonatal cardiomyocytes, ET-1 significantly upregulated the expression and activity of COX-2, which was accompanied by increase in cell surface area and BNP mRNA level. In contrast, ET-1-dependent cardiomyocyte hypertrophy was abolished by COX-2 selective inhibitors, NS-398 and celecoxib, or by COX-2 RNA interference, but the inhibitory effects could be diminished by pretreatment with PGE2. Furthermore, cyclosporin A (CsA) and knockdown of nuclear factor of activated T-cells c3 (NFATc3) inhibited the expression of COX-2 induced by ET-1, and NFATc3 could also bound to the -GGAAA- sequence in the promoter region of rat COX-2 gene, indicating that calcineurin/NFATc3 signaling participated in the transcriptional regulation of COX-2 following ET-1 treatment. These findings provided further insight into the roles of ET-1 in cardiac hypertrophy and suggested a potential therapeutic strategy against cardiac hypertrophy by inhibiting COX-2.