A lthough early reperfusion strategies have dramatically improved survival rates in patients with acute myocardial infarction (MI), an increasing number of patients are at risk of developing heart failure.1 Progressive alterations in cardiac structure (dimensions, mass, and shape) as a result of endogenous repair mechanisms in response to MI are commonly referred to as ventricular remodeling.
2The cardiac repair mechanisms initiated directly after MI are considered as an inflammatory condition that ideally leads to rapid elimination of injurious stimuli and initiation of myocardial healing. The recruitment of immune cells depends on the release of damage-associated molecular patterns that are recognized by receptors on leukocytes and subsequently stimulate the production of proinflammatory cytokines.3 In addition, fragments of the extracellular matrix and complement factors trigger the production of proinflammatory cytokines. 4 These mediators then act on local vascular endothelium, resulting in an increased permeability with subsequent invasion of inflammatory cells, such as neutrophils and monocytes, followed by T cells. 4 A hallmark of ischemic cells is the early release of ATP, normally present within cardiomyocytes in millimolar concentrations, into the extracellular space, which then acts as endogenous danger signal.5 ATP is also well recognized as a find-me signal that guides phagocytes to inflammatory sites, promotes clearance of damaged and apoptotic cells, 6 and acts through specific ATP receptors (P2). ATP can also be directly released from immune cells on activation. 7,8 In addition, ATP released from neutrophils promotes recognition of chemotactic gradients that guides these cells to infected and inflamed tissue.9 Although extracellular ATP is rapidly dephosphorylated, the role of its breakdown product adenosine in modulating the kinetics of immune cell infiltration into the injured heart and its influence on cardiac healing and remodeling after ischemia/reperfusion (I/R) have not been explored in detail.The half-life of extracellular ATP is critically determined by the activity of ectoenzymes, such as various ectonucleoside triphosphate diphosphohydrolases, including CD39 that hydrolyzes ATP to ADP and AMP.10 AMP is further hydrolyzed by alkaline phosphatase and ecto-5′-nucleotidase (CD73) to adenosine, which acts on P1 receptors mediating both anti-and proinflammatory effects, depending on the receptor subtype.11 Four distinct subtypes of P1 receptors have
Integrative Physiology© 2013 American Heart Association, Inc. Objective: Here, we investigated the role of CD73 in postinfarction inflammation, cardiac repair, and remodeling in mice after reperfused myocardial infarction (50-minute ischemia).
Methods and Results: We found that compared with control mice (1) cardiac function in CD73−/− mice more severely declined after infarction (systolic failure with enhanced myocardial edema formation) as determined by MRI and was associated with the persistence of cardiac immune cell subsets, (2) ca...