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

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.