Recombinant Adeno-Associated Virus-Mediated Delivery of MicroRNA-21-3p Lowers Hypertension.
Recombinant Adeno-Associated Virus-Mediated Delivery of MicroRNA-21-3p Lowers Hypertension.
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重组腺相关病毒介导的 MicroRNA-21-3p 递送可降低高血压
DOI：
10.1016/j.omtn.2017.11.007
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发表时间：
2018-06-01
期刊：
影响因子：
--
通讯作者：
Wang DW
中科院分区：
文献类型：
--
作者：
Wang F;Fang Q;Chen C;Zhou L;Li H;Yin Z;Wang Y;Zhao CX;Xiao X;Wang DW
高血压是全球心血管疾病最重要的危险因素。然而，高血压的潜在分子机制是复杂的，在很大程度上仍然是难以捉摸的。在这里，我们描述了一种新的microRNA依赖性高血压治疗策略。首先，我们发现与正常对照组相比，高血压患者和自发性高血压大鼠（SHR）的血浆microRNA-21- 3 p（miR-21- 3 p）水平均显著降低。在一系列分析miR-21- 3 p在高血压中作用的实验中，我们发现静脉内递送重组腺相关病毒（rAAV）介导的miR-21- 3 p表达诱导高血压持续减轻，靶器官损伤显著改善，包括SHR中的心脏肥大和纤维化以及动脉和肾脏纤维化，而miR-21- 3 p坚韧decoys（TuDs）则抵消了上述作用。计算预测结合生化实验表明，miR-21- 3 p介导的降血压效应是通过抑制动脉中的肾上腺α 2B-肾上腺素能受体（ADRA 2B）来调节血管平滑肌细胞（VSMCs）的表型转换而实现的。此外，我们观察到转录因子NF-κB和SRF的激活显著增加了VSMCs中miR-21- 3 p的表达。总之，我们的研究首次确定了miR-21- 3 p在血压控制中的新作用和机制，并为使用rAAV-miR-21- 3 p治疗高血压提供了可能的策略。
Hypertension is the most important risk factor for cardiovascular diseases worldwide. However, the underlying molecular mechanisms of hypertension are complex and remain largely elusive. Here, we described a novel, microRNA-dependent therapeutic strategy for hypertension. First, we found that plasma microRNA-21-3p (miR-21-3p) levels were significantly reduced both in hypertensive patients and spontaneously hypertensive rats (SHRs) when compared with normal controls. In a series of experiments to dissect the role of miR-21-3p in hypertension, we showed that intravenous delivery of recombinant adeno-associated virus (rAAV)-mediated miR-21-3p expression induced a persistent attenuation of hypertension, with marked amelioration of target organ damages, including cardiac hypertrophy and fibrosis and artery and kidney fibrosis in SHRs, whereas miR-21-3p tough decoys (TuDs) counteracted the above effects. Computational prediction coupled with biochemical experiments revealed that the miR-21-3p-mediated hypotensive reduction effect was accomplished by regulating phenotypic switch of vascular smooth muscle cells (VSMCs) via suppression of the adrenal α2B-adrenergic receptor (ADRA2B) in arteries. Furthermore, we observed that activation of transcription factor NF-κB and SRF significantly increased the expression of miR-21-3p in VSMCs. In summary, our study is the first to identify a novel role and mechanism of miR-21-3p in blood pressure control and provides a possible strategy for hypertension therapy using rAAV-miR-21-3p.
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影响因子：
37.8
作者：
Li P;Yin YL;Guo T;Sun XY;Ma H;Zhu ML;Zhao FR;Xu P;Chen Y;Wan GR;Jiang F;Peng QS;Liu C;Liu LY;Wang SX
通讯作者：
Wang SX
影响因子：
11.1
作者：
Degueurce G;D'Errico I;Pich C;Ibberson M;Schütz F;Montagner A;Sgandurra M;Mury L;Jafari P;Boda A;Meunier J;Rezzonico R;Brembilla NC;Hohl D;Kolios A;Hofbauer G;Xenarios I;Michalik L
通讯作者：
Michalik L
影响因子：
15.9
作者：
McDonald, OG;Wamhoff, BR;Owens, GK
通讯作者：
Owens, GK
影响因子：
8.3
作者：
Makaritsis, KP;Johns, C;Gavras, H
通讯作者：
Gavras, H
影响因子：
8.3
作者：
Kopp, Ulla C.;Cicha, Michael Z.;Smith, Lori A.
通讯作者：
Smith, Lori A.