Adenosine A_2A Receptor Regulates microRNA-181b Expression in Aorta: Therapeutic Implications for Large-Artery...

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_2ARs) triggers dissociation of trax from its C-terminus. As A_2ARs are expressed by vascular smooth muscle cells (VSMCs), we investigated whether stimulation of A_2AR 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_2AR 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_2AR activation might contribute to high-salt water-induced aortic stiffening, we assessed the impact of daily treatment with the selective A_2AR 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_2ARs may have therapeutic potential in treating large-artery stiffness.