Modulation of microRNAs in hypertension-induced arterial remodeling through the β1 and β3-adrenoreceptor pathways

Background: Dysregulation of microRNAs (miRNAs) in arterial dysfunction and hypertension has not been extensively investigated yet. This project determined the effects of two anti-hypertensive beta(1) adrenergic selective blockers on miRNA expression in the Dahl Salt Sensitive (DSS) hypertensive rat model. Methods and results: Microarray analysis showed that a set of miRNAs is differently expressed in the aorta of high salt (HS) treated rats with miR-320 increased and miR-26b and -21 decreased. All of these changes were reverted to normal by nebivolol (NEB, a beta(1) selective-blocker and beta(3) activator). The selective beta(3)-adrenoceptor antagonist S-(-)-cyanopindolol (Syc) counteracted the effect of NEB on these miRNAs. Atenolol (ATN, a pure beta(1)-blocker) combined with specific beta(3) agonist BRL37344 restored the expression of all three miRNAs, similar to NEB, while ATN alone had only a partial effect on miR-320 expression. Computational analysis found Insulin Growth Factor-1 Receptor (IGF1R) as a putative target of miR-320, and Phosphatase and tensin homolog on chromosome ten (PTEN) as a putative target of miR-26b and -21. The targets were verified by luciferase reporter assays. Inhibition of miR-320 by an antisense inhibitor or NEB increased IGF1R expression, while miR-320 overexpression reversed the effect of NEB. Overexpression of miR-26b or -21 or NEB decreased PTEN levels, while inhibition of miR-26b or -21 attenuated the effect of NEB. HS diet induced downregulation of IGF1R and upregulation of PTEN in the aorta. NEB normalized the aberrant expression of IGF1R and PTEN and also improved the impairment of vascular AKT/eNOS signaling. Moreover, both NEB and ATN showed to have protective effects on salt-induced hypertension, oxidative stress, and vascular remodeling. NEB had a greater effect than AN. Conclusions: Our data supports a differential miRNA expression profile in salt-induced hypertension. Manipulation of dysregulated miRNAs by beta-blockers may substantially induce alterations of gene expression and prevent arterial dysfunction and remodeling. Published by Elsevier Ltd.