Targeted inhibition of two specific microRNAs in the brainstem prevents the development of hypertension through the cumulative effect of gene network changes [Fig2]

We here test the concept that disease states may result not from a single cause but from small changes in a network that are collectively significant. We recently showed that development of hypertension (HTN) in the spontaneously hypertensive rat (SHR) model of human essential hypertension is accompanied by changes in microRNA expression levels in the brainstem tracking the development of HTN 1,2. This led to the hypothesis that preventing the change in microRNA levels could prevent the development of HTN. We propose that hypertension emerges from a network that has been pushed out of a normotensive equilibrium into a compensatory, pathological state. We show that small perturbations in the gene regulatory networks in the brainstem by selectively blocking two microRNAs highlighted in our previous results, miR-135a and miR-376a, is sufficient to prevent development of hypertension in the SHR model with a 38% reduction in blood pressure after one week persisting to 29% reduction after two weeks with no change in blood pressure in WKY controls at either timepoint. This effect appears driven by only modest, yet sometimes significant, changes in the expression of rate-limiting genes including IL1a, IL1b, Agtr1a, and Dbh among others. Many of these genes are direct targets of these miRNAs, suggesting that the combination of genes that are targeted in the network is responsible for the effect. The demonstration that hypertension is an emergent property of an underlying regulatory network suggests that a new treatment paradigm altogether is needed.本研究旨在验证下述假说：疾病状态并非源于单一诱因，而是源自生物网络中多组微小改变共同累积产生的显著效应。本团队此前的研究显示，在模拟人类原发性高血压的自发性高血压大鼠(spontaneously hypertensive rat, SHR)模型中，高血压(hypertension, HTN)的发生伴随脑干内微RNA(microRNA)表达水平的改变，且该改变随HTN的进展动态同步1,2。这一发现催生了下述假说：阻断微RNA表达水平的异常改变，可阻止HTN的发生发展。本研究提出，高血压的发生是由于某一调控网络偏离正常血压稳态，进入代偿性病理状态所致。本研究证实，通过选择性阻断本团队前期研究中重点关注的两种微RNA——miR-135a与miR-376a，对脑干内基因调控网络施加微小扰动，即可阻止SHR模型中HTN的发生：给药一周后大鼠血压降低38%，该效果在给药两周后仍维持29%的降幅；而Wistar-Kyoto大鼠(WKY)对照组在两个时间点的血压均无显著变化。该效应似乎仅由限速基因表达的轻度（部分情况下为显著）改变所驱动，涉及的基因包括IL1α、IL1β、Agtr1a及Dbh等。上述诸多基因均为这两种微RNA的直接靶标，这表明网络中被靶向的多基因协同作用是该效应的成因。本研究证实高血压是底层调控网络的涌现属性，这提示我们亟需开发全新的高血压治疗范式。