title: Role of the CD39/CD73 Purinergic Pathway in Modulating Arterial Thrombosis in Mice.
abstract: Circulating blood cells and endothelial cells express ectonucleoside triphosphate diphosphohydrolase-1 (CD39) and ecto-5'-nucleotidase (CD73). CD39 hydrolyzes extracellular ATP or ADP to AMP. CD73 hydrolyzes AMP to adenosine. The goal of this study was to examine the interplay between CD39 and CD73 cascade in arterial thrombosis.
  
  
  
  To determine how CD73 activity influences in vivo thrombosis, the time to ferric chloride-induced arterial thrombosis was measured in CD73-null mice. In response to 5% FeCl3, but not to 10% FeCl3, there was a significant decrease in the time to thrombosis in CD73-null mice compared with wild-type mice. In mice overexpressing CD39, ablation of CD73 did not inhibit the prolongation in the time to thrombosis conveyed by CD39 overexpression. However, the CD73 inhibitor α-β-methylene-ADP nullified the prolongation in the time to thrombosis in human CD39 transgenic (hC39-Tg)/CD73-null mice. To determine whether hematopoietic-derived cells or endothelial cell CD39 activity regulates in vivo arterial thrombus, bone marrow transplant studies were conducted. FeCl3-induced arterial thrombosis in chimeric mice revealed a significant prolongation in the time to thrombosis in hCD39-Tg reconstituted wild-type mice, but not on wild-type reconstituted hCD39-Tg mice. Monocyte depletion with clodronate-loaded liposomes normalized the time to thrombosis in hCD39-Tg mice compared with hCD39-Tg mice treated with control liposomes, demonstrating that increased CD39 expression on monocytes protects against thrombosis.
  
  
  
  These data demonstrate that ablation of CD73 minimally effects in vivo thrombosis, but increased CD39 expression on hematopoietic-derived cells, especially monocytes, attenuates in vivo arterial thrombosis.
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Medicine (R.C., E.C., T.N., R.J.G.), Department of Pharmacology (R.J.G.), and Department of Pathology Microbiology and Immunology (R.J.G.), Vanderbilt University, Nashville, TN; Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus (A.R., Z.M.H., R.H., K.S., D.G.W.); Transplant Institute, Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA (S.C.R.); School of Medicine, Deakin University (K.M.D., P.J.C.); Immunology Research Centre, St. Vincent's Hospital (K.M.D.); and Department of Medicine, University of Melbourne, Victoria, Australia (K.M.D., P.J.C.).
authors.forename: Roman
authors.initials: R
authors.lastname: Covarrubias
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Medicine (R.C., E.C., T.N., R.J.G.), Department of Pharmacology (R.J.G.), and Department of Pathology Microbiology and Immunology (R.J.G.), Vanderbilt University, Nashville, TN; Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus (A.R., Z.M.H., R.H., K.S., D.G.W.); Transplant Institute, Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA (S.C.R.); School of Medicine, Deakin University (K.M.D., P.J.C.); Immunology Research Centre, St. Vincent's Hospital (K.M.D.); and Department of Medicine, University of Melbourne, Victoria, Australia (K.M.D., P.J.C.).
authors.forename: Elena
authors.initials: E
authors.lastname: Chepurko
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Medicine (R.C., E.C., T.N., R.J.G.), Department of Pharmacology (R.J.G.), and Department of Pathology Microbiology and Immunology (R.J.G.), Vanderbilt University, Nashville, TN; Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus (A.R., Z.M.H., R.H., K.S., D.G.W.); Transplant Institute, Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA (S.C.R.); School of Medicine, Deakin University (K.M.D., P.J.C.); Immunology Research Centre, St. Vincent's Hospital (K.M.D.); and Department of Medicine, University of Melbourne, Victoria, Australia (K.M.D., P.J.C.).
authors.forename: Adam
authors.initials: A
authors.lastname: Reynolds
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Medicine (R.C., E.C., T.N., R.J.G.), Department of Pharmacology (R.J.G.), and Department of Pathology Microbiology and Immunology (R.J.G.), Vanderbilt University, Nashville, TN; Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus (A.R., Z.M.H., R.H., K.S., D.G.W.); Transplant Institute, Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA (S.C.R.); School of Medicine, Deakin University (K.M.D., P.J.C.); Immunology Research Centre, St. Vincent's Hospital (K.M.D.); and Department of Medicine, University of Melbourne, Victoria, Australia (K.M.D., P.J.C.).
authors.forename: Zachary M
authors.initials: ZM
authors.lastname: Huttinger
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Medicine (R.C., E.C., T.N., R.J.G.), Department of Pharmacology (R.J.G.), and Department of Pathology Microbiology and Immunology (R.J.G.), Vanderbilt University, Nashville, TN; Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus (A.R., Z.M.H., R.H., K.S., D.G.W.); Transplant Institute, Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA (S.C.R.); School of Medicine, Deakin University (K.M.D., P.J.C.); Immunology Research Centre, St. Vincent's Hospital (K.M.D.); and Department of Medicine, University of Melbourne, Victoria, Australia (K.M.D., P.J.C.).
authors.forename: Ryan
authors.initials: R
authors.lastname: Huttinger
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Medicine (R.C., E.C., T.N., R.J.G.), Department of Pharmacology (R.J.G.), and Department of Pathology Microbiology and Immunology (R.J.G.), Vanderbilt University, Nashville, TN; Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus (A.R., Z.M.H., R.H., K.S., D.G.W.); Transplant Institute, Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA (S.C.R.); School of Medicine, Deakin University (K.M.D., P.J.C.); Immunology Research Centre, St. Vincent's Hospital (K.M.D.); and Department of Medicine, University of Melbourne, Victoria, Australia (K.M.D., P.J.C.).
authors.forename: Katherine
authors.initials: K
authors.lastname: Stanfill
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Medicine (R.C., E.C., T.N., R.J.G.), Department of Pharmacology (R.J.G.), and Department of Pathology Microbiology and Immunology (R.J.G.), Vanderbilt University, Nashville, TN; Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus (A.R., Z.M.H., R.H., K.S., D.G.W.); Transplant Institute, Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA (S.C.R.); School of Medicine, Deakin University (K.M.D., P.J.C.); Immunology Research Centre, St. Vincent's Hospital (K.M.D.); and Department of Medicine, University of Melbourne, Victoria, Australia (K.M.D., P.J.C.).
authors.forename: Debra G
authors.initials: DG
authors.lastname: Wheeler
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Medicine (R.C., E.C., T.N., R.J.G.), Department of Pharmacology (R.J.G.), and Department of Pathology Microbiology and Immunology (R.J.G.), Vanderbilt University, Nashville, TN; Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus (A.R., Z.M.H., R.H., K.S., D.G.W.); Transplant Institute, Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA (S.C.R.); School of Medicine, Deakin University (K.M.D., P.J.C.); Immunology Research Centre, St. Vincent's Hospital (K.M.D.); and Department of Medicine, University of Melbourne, Victoria, Australia (K.M.D., P.J.C.).
authors.forename: Tatiana
authors.initials: T
authors.lastname: Novitskaya
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Medicine (R.C., E.C., T.N., R.J.G.), Department of Pharmacology (R.J.G.), and Department of Pathology Microbiology and Immunology (R.J.G.), Vanderbilt University, Nashville, TN; Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus (A.R., Z.M.H., R.H., K.S., D.G.W.); Transplant Institute, Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA (S.C.R.); School of Medicine, Deakin University (K.M.D., P.J.C.); Immunology Research Centre, St. Vincent's Hospital (K.M.D.); and Department of Medicine, University of Melbourne, Victoria, Australia (K.M.D., P.J.C.).
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Medicine (R.C., E.C., T.N., R.J.G.), Department of Pharmacology (R.J.G.), and Department of Pathology Microbiology and Immunology (R.J.G.), Vanderbilt University, Nashville, TN; Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus (A.R., Z.M.H., R.H., K.S., D.G.W.); Transplant Institute, Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA (S.C.R.); School of Medicine, Deakin University (K.M.D., P.J.C.); Immunology Research Centre, St. Vincent's Hospital (K.M.D.); and Department of Medicine, University of Melbourne, Victoria, Australia (K.M.D., P.J.C.).
authors.forename: Karen M
authors.initials: KM
authors.lastname: Dwyer
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Medicine (R.C., E.C., T.N., R.J.G.), Department of Pharmacology (R.J.G.), and Department of Pathology Microbiology and Immunology (R.J.G.), Vanderbilt University, Nashville, TN; Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus (A.R., Z.M.H., R.H., K.S., D.G.W.); Transplant Institute, Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA (S.C.R.); School of Medicine, Deakin University (K.M.D., P.J.C.); Immunology Research Centre, St. Vincent's Hospital (K.M.D.); and Department of Medicine, University of Melbourne, Victoria, Australia (K.M.D., P.J.C.).
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cowan
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Medicine (R.C., E.C., T.N., R.J.G.), Department of Pharmacology (R.J.G.), and Department of Pathology Microbiology and Immunology (R.J.G.), Vanderbilt University, Nashville, TN; Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus (A.R., Z.M.H., R.H., K.S., D.G.W.); Transplant Institute, Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA (S.C.R.); School of Medicine, Deakin University (K.M.D., P.J.C.); Immunology Research Centre, St. Vincent's Hospital (K.M.D.); and Department of Medicine, University of Melbourne, Victoria, Australia (K.M.D., P.J.C.). richard.gumina@vanderbilt.edu.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gumina
mesh_terms: D015720:5'-Nucleotidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000241:Adenosine / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001081:Apyrase / Q000235:genetics / Q000378:metabolism*; D001157:Arterial Occlusive Diseases / Q000097:blood / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D001777:Blood Coagulation; D016026:Bone Marrow Transplantation; D002712:Chlorides; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology; D005290:Ferric Compounds; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D006868:Hydrolysis; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000201:enzymology; D010641:Phenotype; D015539:Platelet Activation; D013927:Thrombosis / Q000097:blood / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D013997:Time Factors; D014162:Transfection
chemical_list: D015703:Antigens, CD; D002712:Chlorides; D005290:Ferric Compounds; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D015720:5'-Nucleotidase; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine; C024555:ferric chloride
keywords: adenosine diphosphate; monocytes; nucleotidase; platelet activation; thrombosis