Cardioprotection by Ecto-5′-Nucleotidase (CD73) and A _2B Adenosine Receptors

Abstract

Background— Ecto-5′-nucleotidase (CD73)–dependent adenosine generation has been implicated in tissue protection during acute injury. Once generated, adenosine can activate cell-surface adenosine receptors (A 1 AR, A 2A AR, A 2B AR, A 3 AR). In the present study, we define the contribution of adenosine to cardioprotection by ischemic preconditioning. Methods and Results— On the basis of observations of CD73 induction by ischemic preconditioning, we found that inhibition or targeted gene deletion of cd73 abolished infarct size-limiting effects. Moreover, 5′-nucleotidase treatment reconstituted cd73 −/− mice and attenuated infarct sizes in wild-type mice. Transcriptional profiling of adenosine receptors suggested a contribution of A 2B AR because it was selectively induced by ischemic preconditioning. Specifically, in situ ischemic preconditioning conferred cardioprotection in A 1 AR −/− , A 2A AR −/− , or A 3 AR −/− mice but not in A 2B AR −/− mice or in wild-type mice after inhibition of the A 2B AR. Moreover, A 2B AR agonist treatment significantly reduced infarct sizes after ischemia. Conclusions— Taken together, pharmacological and genetic evidence demonstrate the importance of CD73-dependent adenosine generation and signaling through A 2B AR for cardioprotection by ischemic preconditioning and suggests 5′-nucleotidase or A 2B AR agonists as therapy for myocardial ischemia.

Up-regulation of A2B adenosine receptor in A2A adenosine receptor knockout mouse coronary artery

“…Previous studies from our group and others found that A 2B AR was up-regulated in ischemic mouse hearts [16,17]. A 2B AR has recently been shown to have cardio-protective properties [18,19] However, A 2B AR-mediated CF regulation under ischemic conditions has not been studied. A comparative study of cardiac ischemia-reperfusion in A2AWT and A2AKO may give us more information about the role of A 2B AR in CF regulation under ischemia, i.e.…”

“…EC 50 values for BAY 60-6583 are 3-10 nM for human A 2B and >10 µM for A 1 and A 2A ARs [18,19]. Protocol for constructing the concentration-response relationship to BAY 60-6583 was the same as for L-NAME concentration-response curves, except the concentration range is from 10 −11 to 10 −5 M.…”

“…Recently, a A 2B AR specific agonist, BAY 60-6583, showed 1000x more specificity to A 2B AR than to A 1 and A 2A AR [18,19], hence provided a valuable tool for our further studies on A 2B AR function.…”

Cardiac purinergic signalling in health and disease

“…In situ ischaemic pre-conditioning conferred cardioprotection in A1R, A2AR and A3R, but not A2BR knockout mice, or in wild-type mice after inhibition of A2BR, and thus, it was suggested that 5′-nucleotidase and A2BR agonists might be considered as therapeutic agents for myocardial ischaemia [554,555]. Activation of A3R protected against myocardial ischaemia-reperfusion injury in mice, an effect which disappeared in A3R knockout mice [529,556,557].…”

Ecto‐5′‐nucleotidase/CD73 enhances endothelial barrier function and sprouting in blood but not lymphatic vasculature

“…Although the lymph was derived from patients with different underlying morbidities, these data thus collectively suggest that the intralymphatic lymphocytes can produce substantial levels of anti-inflammatory adenosine when they are exiting the tissues. CD73 regulates the permeability of blood vessels under inflammatory conditions [7,[11][12][13][14][15][16][17]30]. Thus, the blood vasculature of all studied organs in CD73-deficient mice has been shown to be leakier to small molecules in multiple models of ischemiareperfusion injury and LPS-induced inflammation when compared to WT mice.…”