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.
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.
Authors: Patrick J Schuler; Bernard J C Macatangay; Zenichiro Saze; Edwin K Jackson; Sharon A Riddler; William G Buchanan; Benedict B Hilldorfer; John W Mellors; Theresa L Whiteside; Charles R Rinaldo Journal: AIDS Date: 2013-06-19 Impact factor: 4.177
Authors: Nadia R Sutton; Diane Bouïs; Kris M Mann; Imran M Rashid; Alexandra L McCubbrey; Matt C Hyman; Daniel R Goldstein; Annie Mei; David J Pinsky Journal: Arterioscler Thromb Vasc Biol Date: 2019-10-17 Impact factor: 8.311