Inactivation of CD73 promotes atherogenesis in apolipoprotein E-deficient mice.

Aims CD73 (ecto-5′-nucleotidase) is expressed by a broad range of immune cells and attenuates inflammation in several acute disease models. This study therefore explored the role of CD73-derived adenosine in a model of chronic vascular inflammation such as atherogenesis. Methods and results CD73−/− mice were backcrossed into the apolipoprotein E (ApoE−/−) background. In CD73−/−/ApoE−/− double mutants, atherosclerotic lesion formation was increased by ∼50% compared with ApoE−/−. However, the cellular composition and extracellular matrix of the plaques did not differ. Surprisingly, we found significant activity and expression of CD73 in the plaque of ApoE−/− mice which increased over time. CD73 co-localized with macrophages, Tregs, and cells of mesenchymal origin. Genome-wide microarray analysis of the aorta lacking CD73 revealed upregulation of endothelin-1 (Edn1) mRNA together with changes of genes in lipid metabolism and the Wnt and nuclear factor kappa B pathways. Measurement of plasma levels verified the upregulation of Edn1 in CD73−/− and double mutants. Plasma triglycerides (TG) were also found to be significantly elevated in the CD73−/−/ApoE−/− mice compared with ApoE−/− controls. Conclusion Lack of CD73 promotes atherogenesis most likely by de-inhibition of resident macrophages and T cells. Elevated Edn1 and TG levels may have contributed. This establishes CD73-derived adenosine as a direct or indirect regulator of atherogenesis. [ABSTRACT FROM PUBLISHER]