An antagonism between the AKT and beta-adrenergic signaling pathways mediated through their reciprocal effects on miR-199a-5p.
An antagonism between the AKT and beta-adrenergic signaling pathways mediated through their reciprocal effects on miR-199a-5p.
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DOI：
10.1016/j.cellsig.2010.02.008
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发表时间：
2010-07
影响因子：
4.8
通讯作者：
Abdellatif M
中科院分区：
文献类型：
--
作者：
Rane S;He M;Sayed D;Yan L;Vatner D;Abdellatif M
我们最近报道，在缺氧预处理 (HPC) 过程中，miR-199a-5p 的下调对于诱导其靶标上调是必要且充分的，包括缺氧诱导因子 1α (Hif-1α) 和 Sirt1。相反，其他人和我们都报道了 miR-199a-5p 在心脏肥大期间上调。因此，本研究的目的是描绘调节 miR-199a-5p 及其靶标表达的信号通路，以及它们在缺氧期间心肌细胞存活中的作用。由于 HPC 是通过 AKT 途径的激活介导的，因此我们质疑 AKT 是否足以诱导 miR-199a-5p 的下调。我们目前的研究表明，组成型活性 AKT (caAKT) 的过表达可导致 miR-199a-5p 减少 70%，并与 HiF-1α（10 ± 2 倍）和 Sirt1（4 ± 0.8 倍）的强劲增加相关，而这种增加可通过 miR-199a-5p 的过表达而逆转。同样，胰岛素受体刺激的 AKT 通路激活诱导 miR-199a-5p 下调及其靶标上调。相比之下，体外和体内β-肾上腺素受体（βAR）激活可诱导 miR-199a-5p 增加 1.8-3.5 倍。因此，我们预测 βAR 会拮抗 AKT 诱导的、miR-199a-5p 依赖性的 Hif-1α 和 Sirt1 上调。事实上，在应用 HPC、caAKT 或胰岛素之前用异丙肾上腺素预处理肌细胞，分别导致 Hif-1α 表达减少 87 ± 3%、75 ± 15% 和 100%，并使细胞对缺氧损伤敏感。因此，β-肾上腺素能信号传导的激活通过上调 miR-199a-5p 抵消 AKT 途径的生存效应。
We have recently reported that downregulation of miR-199a-5p is necessary and sufficient for inducing upregulation of its targets, including hypoxia-inducible factor-1alpha (Hif-1α) and Sirt1, during hypoxia preconditioning (HPC). Conversely, others and we have reported that miR-199a-5p is upregulated during cardiac hypertrophy. Thus, the objective of this study was to delineate the signaling pathways that regulate the expression of miR-199a-5p and its targets, and their role in myocyte survival during hypoxia. Since HPC is mediated through activation of the AKT pathway, we questioned if AKT is sufficient for inducing downregulation of miR-199a-5p. Our present study shows that overexpression of a constitutively active AKT (caAKT) induced 70% reduction in miR-199a-5p and was associated with a robust increase in HiF-1α (10 ± 2 fold) and Sirt1 (4 ± 0.8 fold) that was reversed by overexpression of miR-199a-5p. Similarly, insulin receptor-stimulated activation of the AKT pathway induced downregulation of miR-199a-5p and upregulation of its targets. In contrast, β-adrenergic receptor (βAR) activation in vitro and in vivo, induced 1.8-3.5-fold increase in miR-199a-5p. Accordingly, we predicted that βAR would antagonize AKT-induced, miR-199a-5p-dependent, upregulation of Hif-1α and Sirt1. Indeed, pre-treating the myocytes with isoproterenol before applying HPC, caAKT, or insulin resulted in 87 ± 3%, 75 ± 15 %, and 100% reductions in Hif-1α expression, respectively, and sensitized the cells to hypoxic injury. Thus, activation of beta-adrenergic signaling counteracts the survival effects of the AKT pathway via upregulating miR-199a-5p.
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