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: To study markers of purinergic signaling in a cohort of patients with peripheral artery disease (PAD).
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 stable peripheral artery disease (PAD) patients admitted for non-urgent invasive imaging and/or treatment. The major findings were that ATP, ADP, and CD73 values were higher in atherosclerotic patients than in controls without clinically evident PAD (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 PAD progression. Elevated levels of circulating ATP and ADP are especially associated with atherosclerotic diseases of younger age, and smoking. The anti-thrombotic and anti-inflammatory effects of statins may partly be explained by their ability to lower ADP. We suggest that the pro-thrombotic 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 non-smoking peers.
- Received November 24, 2014.
- Revision received January 22, 2015.
- Accepted January 30, 2015.