A cardiac myocyte-restricted Lin28/let-7 regulatory axis promotes hypoxia-mediated apoptosis by inducing the AKT signaling suppressor PIK3IP1.
A cardiac myocyte-restricted Lin28/let-7 regulatory axis promotes hypoxia-mediated apoptosis by inducing the AKT signaling suppressor PIK3IP1.
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DOI：
10.1016/j.bbadis.2015.12.004
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发表时间：
2016-02
期刊：
影响因子：
--
通讯作者：
Bishopric NH
中科院分区：
文献类型：
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作者：
Joshi S;Wei J;Bishopric NH
let-7 家族的 microRNA (miR) 调节关键的细胞功能，包括生存信号、分化、代谢控制和葡萄糖利用。这些功能在心肌缺血期间可能很重要。 MiR-let-7 表达通过多种冗余机制受到严格的时间和空间控制，这些机制可能是阶段、亚型和组织特异性的。确定心脏缺氧调节 miR-let-7 的机制和功能后果。 MiR-let-7a、-7c 和 -7g 在冠状动脉闭塞后早期的成年小鼠心脏中以及在缺氧的新生大鼠心室肌细胞中下调。 Let-7 抑制不需要葡萄糖消耗，并且发生在转录后水平。缺氧还诱导 RNA 结合蛋白 Lin28（let-7 的负调节因子）的产生。缺氧既不会诱导心脏成纤维细胞中的 Lin28 诱导，也不会诱导 miR-let-7 抑制。这两种变化均通过组蛋白脱乙酰酶抑制剂曲古抑菌素 A 的治疗而消除。通过慢病毒转导将 let-7g 恢复到体内缺氧肌细胞和缺血再灌注小鼠心脏中，增强了缺氧诱导的 Akt 磷酸化和激活，并防止缺氧依赖性 caspase 激活和死亡。从机制上讲，通过交联技术，PI3K 的负调节因子磷脂酰肌醇 3' 激酶相互作用蛋白 1 (PIK3IP1) 被确定为 miR-let-7 的新靶标，表明 miR-let-7g 特异性地将 PI3KIP1 靶向心肌细胞 Argonaute 复合体 RISC。最后，在非衰竭和衰竭的人类心肌中，我们发现了 Lin28 和 miR-let-7g 之间以及 miR-let-7g 和 PIK3IP1 之间的特定逆关系。保守的缺氧反应性 Lin28-miR-let-7-PIK3IP1 调节轴对心肌细胞具有特异性，并在心肌缺血损伤期间促进细胞凋亡。
The let-7 family of microRNAs (miRs) regulates critical cell functions, including survival signaling, differentiation, metabolic control and glucose utilization. These functions may be important during myocardial ischemia. MiR-let-7 expression is under tight temporal and spatial control through multiple redundant mechanisms that may be stage-, isoform- and tissue-specific. To determine the mechanisms and functional consequences of miR-let-7 regulation by hypoxia in the heart. MiR-let-7a, -7c and -7g were downregulated in the adult mouse heart early after coronary occlusion, and in neonatal rat ventricular myocytes subjected to hypoxia. Let-7 repression did not require glucose depletion, and occurred at a post-transcriptional level. Hypoxia also induced the RNA binding protein Lin28, a negative regulator of let-7. Hypoxia induced neither Lin28 induction nor miR-let-7 repression in cardiac fibroblasts. Both changes were abrogated by treatment with the histone deacetylase inhibitor trichostatin A. Restoration of let-7g to hypoxic myocytes and to ischemia-reperfused mouse hearts in vivo via lentiviral transduction potentiated the hypoxia-induced phosphorylation and activation of Akt, and prevented hypoxia-dependent caspase activation and death. Mechanistically, phosphotidyl inositol 3’kinase interacting protein 1 (PIK3IP1), a negative regulator of PI3K, was identified as a novel target of miR-let-7 by a crosslinking technique showing that miR-let-7g specifically targets PI3KIP1 to the cardiac myocyte Argonaute complex RISC. Finally, in non-failing and failing human myocardium, we found specific inverse relationships between Lin28 and miR-let-7g, and between miR-let-7g and PIK3IP1. A conserved hypoxia-responsive Lin28-miR-let-7-PIK3IP1 regulatory axis is specific to cardiac myocytes and promotes apoptosis during myocardial ischemic injury.