Adenosine A 2A Receptor Regulates microRNA‐181b Expression in Aorta: Therapeutic Implications for Large‐Artery Stiffness

Abstract

Background The identification of large‐artery stiffness as a major, independent risk factor for cardiovascular disease–associated morbidity and death has focused attention on identifying therapeutic strategies to combat this disorder. Genetic manipulations that delete or inactivate the translin/trax microRNA‐degrading enzyme confer protection against aortic stiffness induced by chronic ingestion of high‐salt water (4%NaCl in drinking water for 3 weeks) or associated with aging. Therefore, there is heightened interest in identifying interventions capable of inhibiting translin/trax RNase activity, as these may have therapeutic efficacy in large‐artery stiffness. Methods and Results Activation of neuronal adenosine A 2A receptors (A 2A Rs) triggers dissociation of trax from its C‐terminus. As A 2A Rs are expressed by vascular smooth muscle cells (VSMCs), we investigated whether stimulation of A 2A R on vascular smooth muscle cells promotes the association of translin with trax and, thereby increases translin/trax complex activity. We found that treatment of A7r5 cells with the A 2A R agonist CGS21680 leads to increased association of trax with translin. Furthermore, this treatment decreases levels of pre‐microRNA‐181b, a target of translin/trax, and those of its downstream product, mature microRNA‐181b. To check whether A 2A R activation might contribute to high‐salt water–induced aortic stiffening, we assessed the impact of daily treatment with the selective A 2A R antagonist SCH58261 in this paradigm. We found that this treatment blocked aortic stiffening induced by high‐salt water. Further, we confirmed that the age‐associated decline in aortic pre‐microRNA‐181b/microRNA‐181b levels observed in mice also occurs in humans. Conclusions These findings suggest that further studies are warranted to evaluate whether blockade of A 2A Rs may have therapeutic potential in treating large‐artery stiffness.