Triiodothyronine Prevents Cardiac Ischemia/Reperfusion Mitochondrial Impairment and Cell Loss by Regulating miR30a/p53 Axis
Triiodothyronine Prevents Cardiac Ischemia/Reperfusion Mitochondrial Impairment and Cell Loss by Regulating miR30a/p53 Axis
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DOI：
10.1210/en.2014-1106
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发表时间：
2014-11-01
期刊：
影响因子：
4.8
通讯作者：
Pitto, Letizia
中科院分区：
文献类型：
--
作者：
Forini, Francesca;Kusmic, Claudia;Pitto, Letizia
线粒体功能障碍是影响心肌细胞在缺血/再灌注损伤中存活的重要因素。在这种情况下，p53激活了多个信号通路，这些信号通路损害了心肌线粒体，促进了细胞死亡。P53是miR-30的有效靶点，其水平在缺血条件下会下降。虽然三碘甲腺原氨酸(T3)可以挽救缺血后线粒体的活性和细胞活力，但关于其在I/R中对P53信号的调节作用尚无相关数据。在我们的模型中，我们验证了一种假设，即早期补充T3通过维持miRNA30a的表达来抑制大鼠I/R后P53的激活并导致死亡。在我们的模型中，T3的输注促进了缺血后心功能的恢复。在分子水平上，T3的有益作用与危险区(AAR)miR-30a表达水平的恢复有关，该表达水平对应于P53基因的下调。随着P53蛋白含量的降低，AAR中Bax的表达减少，线粒体膜去极化受限，线粒体功能得以保留，细胞凋亡和坏死程度降低。此外，在原代培养的新生大鼠心肌细胞中，T3可阻止低氧诱导的miR-30a下调和P53升高。MiR-30a基因敲除大大抑制了T3的调节作用。总体而言，这些数据表明了一种新的T3介导的心脏保护机制，该机制以线粒体为靶点，至少部分通过调节miR30a/p53轴发挥作用。
Mitochondrial dysfunctions critically affect cardiomyocyte survival during ischemia/reperfusion (I/R) injury. In this scenario p53 activates multiple signaling pathways that impair cardiac mitochondria and promote cell death. p53 is a validated target of miR-30 whose levels fall under ischemic conditions. Although triiodothyronine (T3) rescues post-ischemic mitochondrial activity and cell viability, no data are available on its role in the modulation of p53 signaling in I/R. Here we test the hypothesis that early T3 supplementation in rats inhibits the post I/R activation of p53 pro-death cascade through the maintenance of miRNA 30a expression.In our model, T3 infusion improves the recovery of post-ischemic cardiac performance. At the molecular level, the beneficial effect of T3 is associated with restored levels of miR-30a expression in the area at risk (AAR) that correspond to p53 mRNA downregulation. The concomitant decrease in p53 protein content reduces Bax expression and limits mitochondrial membrane depolarization resulting in preserved mitochondrial function and decreased apoptosis and necrosis extent in the AAR. Also in primary cardiomyocyte culture of neonatal rats, T3 prevents both miR-30a downregulation and p53 raise induced by hypoxia. The regulatory effect of T3 is greatly suppressed by miR-30a knockdown. Overall these data suggest a new mechanism of T3-mediated cardioprotection that is targeted to mitochondria and acts, at least in part, through the regulation of miR30a/p53 axis.