miR-182 Modulates Myocardial Hypertrophic Response Induced by Angiogenesis in Heart.
miR-182 Modulates Myocardial Hypertrophic Response Induced by Angiogenesis in Heart.
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DOI：
10.1038/srep21228
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发表时间：
2016-02-18
影响因子：
4.6
通讯作者：
Tirziu D
中科院分区：
文献类型：
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作者：
Li N;Hwangbo C;Jaba IM;Zhang J;Papangeli I;Han J;Mikush N;Larrivée B;Eichmann A;Chun HJ;Young LH;Tirziu D
心肌肥大是对血流动力学需求的适应性反应。虽然血管生成对于支持心脏质量的增加与匹配的血液供应至关重要，但它也可能促进肥大反应。以前，我们发现胎盘生长因子（PlGF）诱导的心脏血管生成，通过内皮源性NO的旁分泌作用促进心肌肥大，其触发G蛋白信号转导调节因子4（RGS 4）的降解，从而激活心肌细胞中的Akt/mTORC 1通路。在这里，我们研究了miRNA是否有助于与心肌血管生成相关的肥大反应的发展。我们发现，miR-182在PlGF小鼠中随着肥大的发展而上调，但当肥大被PlGF和RGS 4的同时表达或eNOS−/−小鼠中的PlGF表达阻断时，则不是这样。抗miR-182处理抑制肥大反应并防止PlGF小鼠和NO处理的心肌细胞中Akt/mTORC 1活化。miR-182通过下调Bcat 2、Foxo 3和Adcy 6的表达调控PlGF小鼠的肥大反应。特别是，Bcat 2的耗竭，确定为一个新的miR-182的目标，促进AktSer 473/p70-S6 KThr 389磷酸化和心肌细胞肥大。LV压力超负荷没有上调miR-182。因此，miR-182是内皮-心肌细胞串扰的新靶点，在血管生成诱导的肥大反应中起重要作用。
Myocardial hypertrophy is an adaptive response to hemodynamic demands. Although angiogenesis is critical to support the increase in heart mass with matching blood supply, it may also promote a hypertrophic response. Previously, we showed that cardiac angiogenesis induced by placental growth factor (PlGF), promotes myocardial hypertrophy through the paracrine action of endothelium-derived NO, which triggers the degradation of regulator of G protein signaling 4 (RGS4) to activate the Akt/mTORC1 pathways in cardiomyocytes. Here, we investigated whether miRNAs contribute to the development of hypertrophic response associated with myocardial angiogenesis. We show that miR-182 is upregulated concurrently with the development of hypertrophy in PlGF mice, but not when hypertrophy was blocked by concomitant expression of PlGF and RGS4, or by PlGF expression in eNOS−/− mice. Anti-miR-182 treatment inhibits the hypertrophic response and prevents the Akt/mTORC1 activation in PlGF mice and NO-treated cardiomyocytes. miR-182 reduces the expression of Bcat2, Foxo3 and Adcy6 to regulate the hypertrophic response in PlGF mice. Particularly, depletion of Bcat2, identified as a new miR-182 target, promotes AktSer473/p70-S6KThr389 phosphorylation and cardiomyocyte hypertrophy. LV pressure overload did not upregulate miR-182. Thus, miR-182 is a novel target of endothelial-cardiomyocyte crosstalk and plays an important role in the angiogenesis induced-hypertrophic response.