Downregulation of miR-199a derepresses hypoxia-inducible factor-1alpha and Sirtuin 1 and recapitulates hypoxia preconditioning in cardiac myocytes.
Downregulation of miR-199a derepresses hypoxia-inducible factor-1alpha and Sirtuin 1 and recapitulates hypoxia preconditioning in cardiac myocytes.
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DOI：
10.1161/circresaha.108.193102
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发表时间：
2009-04-10
影响因子：
20.1
通讯作者：
Abdellatif M
中科院分区：
文献类型：
--
作者：
Rane S;He M;Sayed D;Vashistha H;Malhotra A;Sadoshima J;Vatner DE;Vatner SF;Abdellatif M
微小RNA（MicroRNAs）是转录后基因调节因子，在各种疾病中差异表达，并涉及潜在的发病机制。我们在此报道，在氧张力下降时，心肌细胞中的miR - 199a急剧下调。这种下调是其靶标缺氧诱导因子（Hif）-1α快速上调所必需的。在缺氧期间补充miR - 199a会抑制Hif - 1α的表达及其对p53的稳定作用，从而减少细胞凋亡。另一方面，在常氧状态下敲低miR - 199a会导致Hif - 1α和沉默调节蛋白（Sirtuin，Sirt）1上调，并重现缺氧预处理现象。Sirt1也是miR - 199a的直接靶标，负责下调脯氨酰羟化酶2，而脯氨酰羟化酶2是稳定Hif - 1α所必需的。因此，我们得出结论，miR - 199a是缺氧触发通路的主要调节因子，可用于预处理细胞以抵抗缺氧损伤。此外，这些数据表明了调节缺氧预处理和长寿的两个关键分子之间存在功能联系。
MicroRNAs are posttranscriptional gene regulators that are differentially expressed during various diseases and have been implicated in the underlying pathogenesis. We report here that miR-199a is acutely downregulated in cardiac myocytes on a decline in oxygen tension. This reduction is required for the rapid upregulation of its target, hypoxia-inducible factor (Hif)-1α. Replenishing miR-199a during hypoxia inhibits Hif-1α expression and its stabilization of p53 and, thus, reduces apoptosis. On the other hand, knockdown of miR-199a during normoxia results in the upregulation of Hif-1α and Sirtuin (Sirt)1 and reproduces hypoxia preconditioning. Sirt1 is also a direct target of miR-199a and is responsible for downregulating prolyl hydroxylase 2, required for stabilization of Hif-1α. Thus, we conclude that miR-199a is a master regulator of a hypoxia-triggered pathway and can be exploited for preconditioning cells against hypoxic damage. In addition, the data demonstrate a functional link between 2 key molecules that regulate hypoxia preconditioning and longevity.