Aberrant circulating levels of purinergic signaling markers are associated with several key aspects of peripheral atherosclerosis and thrombosis.
RATIONALE
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.


METHODS AND 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.
['Jalkanen|Juho|J|', 'Yegutkin|Gennady G|GG|', 'Hollmén|Maija|M|', 'Aalto|Kristiina|K|', 'Kiviniemi|Tuomas|T|', 'Salomaa|Veikko|V|', 'Jalkanen|Sirpa|S|', 'Hakovirta|Harri|H|']
D015720:5'-Nucleotidase D000244:Adenosine Diphosphate D000255:Adenosine Triphosphate D000328:Adult D000367:Age Factors D000368:Aged D000369:Aged, 80 and over D000469:Alkaline Phosphatase D000806:Angiotensin-Converting Enzyme Inhibitors D015703:Antigens, CD D001081:Apyrase D016477:Artifacts D050197:Atherosclerosis D015415:Biomarkers D002908:Chronic Disease D015897:Comorbidity D018450:Disease Progression D004363:Drug Utilization D005260:Female D005387:Finland D058851:GPI-Linked Proteins D006801:Humans D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors D006973:Hypertension D000860:Hypoxia D008297:Male D008875:Middle Aged D008955:Models, Cardiovascular D058729:Peripheral Arterial Disease D058921:Purinergic P2Y Receptor Antagonists D012307:Risk Factors D015290:Second Messenger Systems D012907:Smoking D019851:Thrombophilia
atherosclerosis thrombosis smoking adenosine adenosine diphosphate adenosine triphosphate receptors, purinergic P1