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.

高血压是全世界心血管疾病最重要的危险因素。但是，高血压的潜在分子机制很复杂，并且仍然难以捉摸。在这里，我们描述了一种新颖的依赖microRNA的高血压治疗策略。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（SHRs）的血浆microRNA-21-3p（miR-21-3p）水平均显着降低。在剖析miR-21-3p在高血压中的作用的一系列实验中，我们显示了静脉内递送重组腺相关病毒（rAAV）介导的miR-21-3p表达诱导高血压的持续缓解，并有明显改善目标器官损害，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-21-3p强韧诱饵（TuDs）抵消了上述影响。计算预测结合生化实验表明，miR-21-3p介导的降压作用是通过抑制肾上腺α2B-肾上腺素能受体（VSMC）的表型转换来实现的，从而实现了降压作用。ADRA2B）在动脉中。此外，我们观察到转录因子NF-κB和SRF的激活显着增加了VSMC中miR-21-3p的表达。总之，我们的研究是第一个发现miR-21-3p在血压控制中的新作用和机制的研究，并为使用rAAV-miR-21-3p进行高血压治疗提供了可能的策略。