重组腺相关病毒介导的miR-21-3p在高血压中的作用及机制研究

Hypertension is the most important risk factor for a wide variety of cardiovascular diseases. Prevention and control of hypertension can significantly reduce the morbidity and mortality of cardiovascular diseases. However, the control rate of hypertension is very low right now，and the morbidity of hypertension is still increasing year by year, so some new treatments are urgently needed for treatment of hypertension. MicroRNAs are endogenous small noncoding RNAs, and they can regulate the expressions of protein-coding genes at the posttranscriptional level. Recent evidences demonstrated that miRNAs play prominent roles in various cardiovascular diseases. In our previous studies, the differential expression of plasma miR-21-3p were found in both hypertension patients and hypertensive animal models. Recombinant adeno-associated virus mediated delivery of miR-21-3p induced a persistent and remarkable attenuation of hypertension in spontaneously hypertensive rats (SHRs). However the mechanism of the hypotensive effect of miR-21-3p is still unknown. In order to comprehensively clarify the functions and mechanisms of miR-21-3p in hypertension, this study focuses on clarifying the role and mechanisms of miR-21-3p in hypertension and identifying the upstream and downstream molecular signaling targets of miR-21-3p in hypertension. This project will provide important theoretical basis for miRNA targeted therapy for prevention and treatment of hypertension.

高血压是心脑血管疾病最重要的危险因素，预防和控制高血压能显著降低心脑血管疾病的发病率和死亡率。但目前高血压的控制率极低，高血压的发病率仍在逐年增加，因而迫切需要寻求新的治疗方法。MicroRNA是一类非编码的小RNA，它能在转录后水平调控基因的表达，越来越多的证据表明miRNAs在心血管疾病中的发挥着重要作用。我们的前期研究发现血浆miR-21-3p在高血压患者及高血压模式动物中存在差异性表达，重组腺相关病毒介导的miR-21-3p能显著降低自发性高血压大鼠（SHRs）血压，但其机制尚未明确。本项目重在探讨miR-21-3p对高血压模式动物(SHRs)血压的影响及其具体的上下游分子信号通路，从而阐明miR-21-3p在高血压中的作用及机制，为高血压的防治提供新的思路，为研究高血压的microRNA靶向治疗药物提供新的理论依据。

高血压是严重危害人类公共安全的慢性非传染性疾病，全球罹患高血压的患者超过11亿，它是心脑血管疾病最为重要的危险因素。高血压的发病机制极为复杂，目前尚未被完全阐明。本研究阐明了由microRNAs介导高血压治疗新策略。首先，我们在高血压患者以及高血压模式动物中发现了存在显著差异性表达的miR-21-3p。随后，我们开展了一系列实验以明确miR-21-3p在高血压发生发展中的作用。我们的研究发现rAAV介导的miR-21-3p基因投递能长期且显著地降低自发性高血压大鼠的血压，同时能够明显的改善由高血压引起的靶器官损害，包括改善SHR大鼠主动脉及小动脉的舒缩功能，抑制心肌细胞的肥厚及纤维化，大动脉、小动脉的纤维化，肾脏的纤维化。而miR-21-3p吸附序列TuDs能逆转miR-21-3p引起的降压和器官保护效应。通过深入的机体探讨，我们发现miR-21-3p是通过直接调控ADRA2B基因的表达，抑制血管平滑肌细胞由收缩表型向分泌表型的转换，改善SHR大鼠血管重构，从而降低机体的血压。与此同时，我们还明确了miR-21-3p上游的转录调控机制，研究发现转录因子NF-kB和SRF通过与miR-21-3p上游启动子序列直接结合，可显著增强血管平滑肌细胞miR-21-3p的表达。综上所述，我们的研究揭示了miR-21-3p参与调控机体血压的新机制，这为高血压的分子靶向治疗提供了新靶点和理论依据。