title: Aberrant circulating levels of purinergic signaling markers are associated with several key aspects of peripheral atherosclerosis and thrombosis.
abstract: BACKGROUND
  Purinergic signaling plays an important role in inflammation and vascular integrity, but little is known about purinergic mechanisms during the pathogenesis of atherosclerosis in humans.
  
  
  OBJECTIVE
  The objective of this study is to study markers of purinergic signaling in a cohort of patients with peripheral artery disease.
  
  
  RESULTS
  Plasma ATP and ADP levels and serum nucleoside triphosphate diphosphohydrolase-1 (NTPDase1/CD39) and ecto-5'-nucleotidase/CD73 activities were measured in 226 patients with stable peripheral artery disease admitted for nonurgent invasive imaging and treatment. The major findings were that ATP, ADP, and CD73 values were higher in atherosclerotic patients than in controls without clinically evident peripheral artery disease (P<0.0001). Low CD39 activity was associated with disease progression (P=0.01). In multivariable linear regression models, high CD73 activity was associated with chronic hypoxia (P=0.001). Statin use was associated with lower ADP (P=0.041) and tended to associate with higher CD73 (P=0.054), while lower ATP was associated with the use of angiotensin receptor blockers (P=0.015).
  
  
  CONCLUSIONS
  Purinergic signaling plays an important role in peripheral artery disease progression. Elevated levels of circulating ATP and ADP are especially associated with atherosclerotic diseases of younger age and smoking. The antithrombotic and anti-inflammatory effects of statins may partly be explained by their ability to lower ADP. We suggest that the prothrombotic nature of smoking could be a cause of elevated ADP, and this may explain why cardiovascular patients who smoke benefit from platelet P2Y12 receptor antagonists more than their nonsmoking peers.
authors: From the Department of Vascular Surgery (J.J., H.H.) and Heart Center (T.K.), Turku University Hospital, Turku, Finland; Medicity Research Laboratory, Department of Microbiology and Immunology, University of Turku, Turku, Finland (G.G.Y., M.H., K.A., S.J.); and National Institute for Health and Welfare, Helsinki, Finland (V.S.).
authors: Juho
authors: J
authors: Jalkanen
authors: From the Department of Vascular Surgery (J.J., H.H.) and Heart Center (T.K.), Turku University Hospital, Turku, Finland; Medicity Research Laboratory, Department of Microbiology and Immunology, University of Turku, Turku, Finland (G.G.Y., M.H., K.A., S.J.); and National Institute for Health and Welfare, Helsinki, Finland (V.S.).
authors: Gennady G
authors: GG
authors: Yegutkin
authors: From the Department of Vascular Surgery (J.J., H.H.) and Heart Center (T.K.), Turku University Hospital, Turku, Finland; Medicity Research Laboratory, Department of Microbiology and Immunology, University of Turku, Turku, Finland (G.G.Y., M.H., K.A., S.J.); and National Institute for Health and Welfare, Helsinki, Finland (V.S.).
authors: Maija
authors: M
authors: Hollmén
authors: From the Department of Vascular Surgery (J.J., H.H.) and Heart Center (T.K.), Turku University Hospital, Turku, Finland; Medicity Research Laboratory, Department of Microbiology and Immunology, University of Turku, Turku, Finland (G.G.Y., M.H., K.A., S.J.); and National Institute for Health and Welfare, Helsinki, Finland (V.S.).
authors: Kristiina
authors: K
authors: Aalto
authors: From the Department of Vascular Surgery (J.J., H.H.) and Heart Center (T.K.), Turku University Hospital, Turku, Finland; Medicity Research Laboratory, Department of Microbiology and Immunology, University of Turku, Turku, Finland (G.G.Y., M.H., K.A., S.J.); and National Institute for Health and Welfare, Helsinki, Finland (V.S.).
authors: Tuomas
authors: T
authors: Kiviniemi
authors: From the Department of Vascular Surgery (J.J., H.H.) and Heart Center (T.K.), Turku University Hospital, Turku, Finland; Medicity Research Laboratory, Department of Microbiology and Immunology, University of Turku, Turku, Finland (G.G.Y., M.H., K.A., S.J.); and National Institute for Health and Welfare, Helsinki, Finland (V.S.).
authors: Veikko
authors: V
authors: Salomaa
authors: From the Department of Vascular Surgery (J.J., H.H.) and Heart Center (T.K.), Turku University Hospital, Turku, Finland; Medicity Research Laboratory, Department of Microbiology and Immunology, University of Turku, Turku, Finland (G.G.Y., M.H., K.A., S.J.); and National Institute for Health and Welfare, Helsinki, Finland (V.S.). sirpa.jalkanen@utu.fi.
authors: Sirpa
authors: S
authors: Jalkanen
authors: From the Department of Vascular Surgery (J.J., H.H.) and Heart Center (T.K.), Turku University Hospital, Turku, Finland; Medicity Research Laboratory, Department of Microbiology and Immunology, University of Turku, Turku, Finland (G.G.Y., M.H., K.A., S.J.); and National Institute for Health and Welfare, Helsinki, Finland (V.S.).
authors: Harri
authors: H
authors: Hakovirta
mesh_terms: D015720:5'-Nucleotidase / Q000097:blood*; D000244:Adenosine Diphosphate / Q000097:blood*; D000255:Adenosine Triphosphate / Q000097:blood*; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D015703:Antigens, CD / Q000097:blood*; D001081:Apyrase / Q000097:blood*; D016477:Artifacts; D050197:Atherosclerosis / Q000097:blood* / Q000453:epidemiology; D015415:Biomarkers; D002908:Chronic Disease; D015897:Comorbidity; D018450:Disease Progression; D004363:Drug Utilization; D005260:Female; D005387:Finland / Q000453:epidemiology; D058851:GPI-Linked Proteins / Q000097:blood; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006973:Hypertension / Q000097:blood / Q000188:drug therapy / Q000453:epidemiology; D000860:Hypoxia / Q000097:blood; D008297:Male; D008875:Middle Aged; D008955:Models, Cardiovascular; D058729:Peripheral Arterial Disease / Q000097:blood* / Q000453:epidemiology; D058921:Purinergic P2Y Receptor Antagonists / Q000627:therapeutic use; D012307:Risk Factors; D015290:Second Messenger Systems; D012907:Smoking / Q000009:adverse effects / Q000097:blood / Q000453:epidemiology; D019851:Thrombophilia / Q000097:blood* / Q000453:epidemiology / Q000209:etiology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D015703:Antigens, CD; D015415:Biomarkers; D058851:GPI-Linked Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000469:Alkaline Phosphatase; D015720:5'-Nucleotidase; C548241:NT5E protein, human; D001081:Apyrase; C067869:CD39 antigen
keywords: adenosine; adenosine diphosphate; adenosine triphosphate; atherosclerosis; receptors, purinergic P1; smoking; thrombosis