Role of miR206 in genistein-induced rescue of pulmonary hypertension in monocrotaline model.
Role of miR206 in genistein-induced rescue of pulmonary hypertension in monocrotaline model.
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DOI：
10.1152/japplphysiol.00699.2014
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发表时间：
2015-10
影响因子：
3.3
通讯作者：
Salil Sharma;S. Umar;Alex Centala;M. Eghbali
中科院分区：
文献类型：
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作者：
Salil Sharma;S. Umar;Alex Centala;M. Eghbali
肺动脉高压（PH）是一种与平滑肌细胞增生和肺微血管收缩相关的进行性肺部疾病，可导致肺动脉压升高、右心室衰竭和死亡。我们之前已经证明染料木素通过显著改善肺和心脏功能来挽救先前存在的既定PH。[1]张晓明，张晓明，张晓明，张晓明，等。中华人民共和国高血压病杂志（英文版），2012。在这里，我们研究了microRNAs （miRs）在染料木素（染料木素）在MCT诱导的大鼠PH中的拯救作用。我们对对照组、PH组和染料木黄酮拯救组肺样本的miR微阵列分析显示，miR206被PH强烈上调至11倍，通过染料木黄酮处理完全正常化到对照水平。接下来，我们研究了miR206的敲低是否可以逆转先前存在的PH值。在雄性大鼠中，60 mg/kg的MCT诱导PH值，大鼠在第17、21和26天接受了三次气管内剂量的miR206安他哥米（10 mg/kg体重）或混乱的miR控制。miR206基因敲低可显著改善心肺功能，PH值右心室压由61.2±5.4 mmHg显著降低至38.6±3.61 mmHg。在ph下，右心室肥厚指数从0.59±0.037降至0.35±0.04。miR206的敲低逆转了ph诱导的肺血管重塑，并与ph诱导的肺毛细血管损失的恢复和血管内皮生长因子A的诱导表达有关。综上所述，miR206安他哥米治疗可能通过刺激肺血管生成来改善MCT大鼠模型的心肺功能和结构，并挽救先前存在的严重PH。
Pulmonary hypertension (PH) is a progressive lung disease associated with proliferation of smooth muscle cells and constriction of lung microvasculature, leading to increased pulmonary arterial pressure, right ventricular failure, and death. We have previously shown that genistein rescues preexisting established PH by significantly improving lung and heart function. (Matori H, Umar S, Nadadur RD, Sharma S, Partow-Navid R, Afkhami M, Amjedi M, Eghbali M. Hypertension 60: 425-430, 2012). Here, we have examined the role of microRNAs (miRs) in the rescue action of genistein in monocrotaline (MCT)-induced PH in rats. Our miR microarray analysis on the lung samples from control, PH, and genistein-rescue group revealed that miR206, which was robustly upregulated to ∼11-fold by PH, was completely normalized to control levels by genistein treatment. Next, we examined whether knockdown of miR206 could reverse preexisting established PH. PH was induced in male rats by 60 mg/kg of MCT, and rats received three intratracheal doses of either miR206 antagomir (10 mg/kg body wt) or scrambled miR control at days 17, 21, and 26. Knockdown of miR206 resulted in significant improvement in the cardiopulmonary function, as right ventricular pressure was significantly reduced to 38.6 ± 3.61 mmHg from 61.2 ± 5.4 mmHg in PH, and right ventricular hypertrophy index was decreased to 0.35 ± 0.04 from 0.59 ± 0.037 in PH. Knockdown of miR206 reversed PH-induced pulmonary vascular remodeling in vivo and was associated with restoration of PH-induced loss of capillaries in the lungs and induction of vascular endothelial growth factor A expression. In conclusion, miR206 antagomir therapy improves cardiopulmonary function and structure and rescues preexisting severe PH in MCT rat model possibly by stimulating angiogenesis in the lung.