CD73 Modulation of Atherosclerotic Plaque in Apolipoprotein E Deficient Mice
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CD73 (ecto-5 ' -nucleotidase) is a glycosyl-phosphatidylinositol (GPI)-linked enzyme that catalyzes the extracellular dephosphorylation of AMP to adenosine. Extracellular adenosine regulates inflammation through controlling chemokine release and adhesion marker expression. Previous literature has shown the adenosine generated by CD73 activity is significant in preventing damage caused by over-inflammation. In this study we tested the hypothesis that adenosine produced by CD73 activity was significant in attenuating the progression of atherosclerosis, a chronic, inflammatory, cardiovascular disease. Cardiovascular disease is currently the number one cause of death in the Western World. The Apolipoprotein E (ApoE) deficient murine model of atherosclerosis was used for in vivo study of the disease as it creates an inability to process LDL and VLDL cholesterol, resulting in spontaneous atherosclerosis. ApoE-/- mice were crossed with CD73-/- mice to create ApoE-/-CD73-/- double-knockout mice. Surface area of atherosclerotic plaques was compared between ApoE-/- and ApoE-/-CD73-/- mice to quantify progression of atherosclerosis for age groups between 12 and 52 weeks. Unexpectedly, a deficiency of CD73 in ApoE background mice was found to significantly slow the progression of atherosclerosis over time, identifying CD73 as a critical enzyme in the progression of atherosclerosis through a novel and still undetermined mechanism. RT -PCR analysis of adenosine kinase and deoxycytidine kinase, two transferases that decrease extracellular adenosine concentrations, showed upregulation of both enzymes in ApoE-/-CD73-/- mice, suggesting compensatory mechanisms related to adenosine production are not responsible for the unexpected results. A better understanding of the effects of adenosine and CD73 on atherosclerosis may lead to targeted treatments for cardiovascular disease.