Direct Delivery of MicroRNA96 to the Lungs Reduces Progression of Sugen/Hypoxia-Induced Pulmonary Hypertension in the Rat.
Direct Delivery of MicroRNA96 to the Lungs Reduces Progression of Sugen/Hypoxia-Induced Pulmonary Hypertension in the Rat.
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DOI：
10.1016/j.omtn.2020.09.002
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发表时间：
2020-12-04
期刊：
影响因子：
--
通讯作者：
MacLean MR
中科院分区：
文献类型：
--
作者：
Docherty CK;Denver N;Fisher S;Nilsen M;Hillyard D;Openshaw RL;Labazi H;MacLean MR
5HT1b受体(5HT1BR)参与了5-羟色胺在肺动脉高压中的致病作用。在这里，我们确定了一种直接进入肺部的microRNA96(MiR96)模拟物对大鼠严重肺动脉高压的影响。雌性大鼠给予SUGEN(30 mg/kg)，然后进行3周的低压低氧。在常氧状态下，大鼠气管内注射5HT1BR拮抗剂SB216641(7.5g/kg/d，连续3周)，miR96，或扰乱序列(每只大鼠50μg)，每周一次，连续3周。采用定量逆转录聚合酶链式反应(qRT-PCR)检测心脏血流动力学、肺血管重塑、基因表达，用Western印迹和ELISA法检测原位杂交和蛋白表达。肺组织中5HT1BR蛋白表达下调，肺组织中miR96表达增加。MiR96可减少右室收缩压、肺动脉重塑、右室肥厚和闭塞性肺病变的发生。重要的是，miR96没有非靶点效应，也不影响肝肾功能的纤维化标志物。总之，将miR96直接输送到肺部是有效的，可以减少SUGEN/低氧诱导的肺动脉高压的进展，并且没有测量到的非靶点效应。MiR96可能通过下调5HT1BR的表达而成为治疗肺动脉高压的新药物。5-羟色胺通过5HT1b受体发挥作用，参与了肺动脉高压的病理生理过程。在肺动脉高压模型中，miR96直接进入肺内可减少肺组织5HT1b受体的表达，逆转肺动脉高压，而不会引起任何炎症或肝肾功能的丧失。
The 5HT1B receptor (5HT1BR) contributes to the pathogenic effects of serotonin in pulmonary arterial hypertension. Here, we determine the effect of a microRNA96 (miR96) mimic delivered directly to the lungs on development of severe pulmonary hypertension in rats. Female rats were dosed with sugen (30 mg/kg) and subjected to 3 weeks of hypobaric hypoxia. In normoxia, rats were dosed with either a 5HT1BR antagonist SB216641 (7.5 mg/kg/day for 3 weeks), miR96, or scramble sequence (50 μg per rat), delivered by intratracheal (i.t) administration, once a week for 3 weeks. Cardiac hemodynamics were determined, pulmonary vascular remodeling was assessed, and gene expression was assessed by qRT-PCR, and in situ hybridization and protein expression were assessed by western blot and ELISA. miR96 expression was increased in pulmonary arteries and associated with a downregulation of the 5HT1BR protein in the lung. miR96 reduced progression of right ventricular systolic pressure, pulmonary arterial remodeling, right ventricular hypertrophy, and the occurrence of occlusive pulmonary lesions. Importantly, miR96 had no off-target effects and did not affect fibrotic markers of liver and kidney function. In conclusion, direct delivery of miR96 to the lungs was effective, reducing progression of sugen/hypoxia-induced pulmonary hypertension with no measured off-target effects. miR96 may be a novel therapy for pulmonary arterial hypertension, acting through downregulation of 5HT1BR. Serotonin, acting through the 5HT1B receptor contributes to the pathophysiology of pulmonary hypertension. In a model of pulmonary hypertension, miR96 delivered directly to the lungs decreased expression of the lung 5HT1B receptor and reversed pulmonary hypertension without causing any inflammation or loss of liver or kidney function.
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DOI：
10.1124/jpet.116.237933
发表时间：
2017-02-01
影响因子：
3.5
作者：
Aiello, Robert J.;Bourassa, Patricia-Ann;Paralkar, Vishwas
通讯作者：
Paralkar, Vishwas
影响因子：
5.4
作者：
Docherty, Craig K.;Nilsen, Margaret;MacLean, Margaret R.
通讯作者：
MacLean, Margaret R.
影响因子：
24
作者：
Humbert, M;Morrell, NW;Rabinovitch, M
通讯作者：
Rabinovitch, M
影响因子：
2.6
作者：
MacLean MMR
通讯作者：
MacLean MMR
影响因子：
4.8
作者：
Liu, Yinglin;Ren, Wenying;Fanburg, Barry L.
通讯作者：
Fanburg, Barry L.