Treating the Network: Application of a Combination of Two microRNA Inhibitors to the Brainstem Prevents Hypertension Development in the Spontaneously Hypertensive Rat

Abstract

We here test the concept that a disturbed function or disease state may result not from a single cause but from small changes in a network that are collectively significant, and that treatment might aim to correct these collective changes. We recently showed that development of hypertension (HTN) in the spontaneously hypertensive rat (SHR) model of human essential hypertension is accompanied by small changes in gene expression within a gene regulatory network, and that these changes potentially result from changes in microRNA expression levels tracking the development of HTN. These results led to the hypothesis that preventing the change in microRNA levels might prevent the development of HTN. We propose that hypertension is an emergent property of a network that has been pushed out of a normotensive equilibrium into a compensatory, yet ultimately pathological, state. In this work, we show that small perturbations in the gene regulatory networks in the brainstem by selectively blocking two microRNAs is sufficient to prevent development of hypertension in the SHR model. Furthermore, this effect appears driven by only modest changes in the expression of rate‐limiting genes, some of which are targets of these miRNAs, suggesting that the combination of genes that are targeted in the network is responsible for the effect rather than just one gene or another. While the use of anti‐sense oligonucleotides to treat hypertension is itself novel, the demonstration that hypertension is an emergent property an underlying network suggests that a new treatment paradigm altogether is needed.Support or Funding InformationFunding Sources: T32 AA007463‐28; U01 HL133360; R01 HL111621; SPARC‐OT2‐OD023848This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.