Abstract 16362: Adenosine Deaminase 2 Inhibits Adenosine-Driven Neutrophil Activation in Atherosclerosis
Introduction: In recent years, many studies have implicated activation of neutrophils in the process of atherosclerosis. Neutrophils can be activated by adenosine which is commonly found in atherosclerotic lesions. Adenosine Deaminase 2 (ADA2) converts adenosine into inosine and patients afflicted by loss-of-function mutations in ADA2 suffer from various vascular and inflammatory phenotypes related to disturbed neutrophil biology. We hypothesized that ADA2 plays a role in atherosclerosis development by regulating neutrophil activation.
Methods and Results: Plasma levels of ADA2 in humans were negatively correlated with neutrophil activation as measured by circulating levels of myeloperoxidase (MPO). Immunohistochemical staining of human carotid arteries showed that ADA2 protein is present in human atherosclerotic lesions. Subsequent whole mount in situ hybridization indicated that ADA2 RNA is produced in atherosclerotic lesions. Mass spectrometry imaging was used to visualize the spatial distribution of adenosine and inosine in human carotid lesions which was combined with immunohistochemistry of ADA2. Regions that showed high expression of ADA2 were devoid of adenosine but were highly enriched in inosine, suggesting that ADA2 converts adenosine in inosine in human atherosclerosis. To assess the effect of ADA2 in vitro, freshly harvested human neutrophils were stimulated with adenosine. Adenosine strongly induced neutrophil activation as seen by increased release of the atherosclerosis promoting factors MPO (457±24%,n=5), MMP9 (215±12%,n=5), and neutrophil extracellular traps (NETs) (381±18%,n=5). Co-stimulation with ADA2 resulted in a reduction of MPO (309±7%,n=5), MMP9 (136±8%,n=5), and NETs (293±11%,n=5).
Conclusion: These results indicate, for the first time, that ADA2 inhibits neutrophil activation by the conversion of adenosine to inosine. This novel function and the presence in human atherosclerotic lesions points to a role in the development of atherosclerosis and may provide new approaches in the treatment of cardiovascular disease.
Author Disclosures: D. van Keulen: Employment; Significant; Quorics B.V.. S. Aldi: None. G.R. Hamm: None. R. Ait-Belkacem: None. J. Stauber: None. K. Holmstrøm: None. B.S. Nielsen: None. E. Hurt-Camejo: None. J.N. Lindeman: None. H.M. Princen: None. G. Pasterkamp: None. U. Hedin: None. A.J. van Gool: None. D. Tempel: Employment; Significant; Quorics B.V..
- © 2017 by American Heart Association, Inc.