Repression of miR-142 by p300 and MAPK is required for survival signalling via gp130 during adaptive hypertrophy.
Repression of miR-142 by p300 and MAPK is required for survival signalling via gp130 during adaptive hypertrophy.
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P300和MAPK对MIR-142的抑制是在自适应肥大期间通过GP130的存活信号所必需的。
DOI：
10.1002/emmm.201200234
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发表时间：
2012-07
影响因子：
11.1
通讯作者：
Bishopric, Nanette H.
中科院分区：
文献类型：
--
作者：
Sharma, Salil;Liu, Jing;Wei, Jianqin;Yuan, Huijun;Zhang, Taifang;Bishopric, Nanette H.
心脏工作负荷的增加，最终导致肥大，产生氧化应激，因此需要激活生存和生长信号通路。在这里，我们想描述miR-142的调节因子，靶点和机制作用，miR-142是一种在肥大过程中负调控的microRNA（miRNA）。我们发现，在培养的心肌细胞中，在体内心脏肥大模型和人类心肌病心脏中，miRNA-142 - 3p和-5p都受到血清衍生生长因子的抑制。miR-142水平与乙酰转移酶p300和MAPK活性水平呈负相关。当存在时，miR-142通过直接靶向节点调节因子p300和gp130来抑制存活和生长途径。miR-142还有效地抑制NF-κ B途径的多种组分，防止精氨酸介导的NO产生并阻断α-辅肌动蛋白的翻译。在肥大生长过程中，miR-142的强制表达诱导了广泛的细胞凋亡和心功能障碍;相反，miR-142的缺失完全挽救了小鼠心力衰竭模型中的心功能。miR-142的下调是在心脏生长过程中响应血流动力学应激而启动精氨酸介导的存活信号传导所必需的，并且是适应性肥大的关键因素。
An increase in cardiac workload, ultimately resulting in hypertrophy, generates oxidative stress and therefore requires the activation of both survival and growth signal pathways. Here, we wanted to characterize the regulators, targets and mechanistic roles of miR-142, a microRNA (miRNA) negatively regulated during hypertrophy. We show that both miRNA-142-3p and -5p are repressed by serum-derived growth factors in cultured cardiac myocytes, in models of cardiac hypertrophy in vivo and in human cardiomyopathic hearts. Levels of miR-142 are inversely related to levels of acetyltransferase p300 and MAPK activity. When present, miR-142 inhibits both survival and growth pathways by directly targeting nodal regulators p300 and gp130. MiR-142 also potently represses multiple components of the NF-κB pathway, preventing cytokine-mediated NO production and blocks translation of α-actinin. Forced expression of miR-142 during hypertrophic growth induced extensive apoptosis and cardiac dysfunction; conversely, loss of miR-142 fully rescued cardiac function in a murine heart failure model. Downregulation of miR-142 is required to enable cytokine-mediated survival signalling during cardiac growth in response to haemodynamic stress and is a critical element of adaptive hypertrophy.
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