Abstract 16089: CD73 Expressed on Leukocytes Protects the Mouse Heart from Adverse Cardiac Remodeling by Inhibiting Local Inflammation and Scar Formation
Myocardial injury during infarction leads to a massive release of pro-inflammatory nucleotides, the extracellular degradation of which is controlled by a cascade of ectoenzymes. Ecto-5’-nucleotidase (CD73) catalyzes the final conversion to adenosine, a potent anti-inflammatory autacoid. The aim of this study was to investigate the role of CD73-derived adenosine in cardiac healing and remodeling after severe ischemia and subsequent reperfusion (I/R). Wild-type (WT) and CD73-deficient mice (CD73-/-) underwent 50 min occlusion of the left anterior descending artery (LAD). Functional parameters were measured by cine 1H MRI and monocyte infiltration by 19F MRI in vivo. In separate experiments immune cells were isolated from myocardial tissue and the abundance of leukocyte subtypes was analyzed by flow cytometry before and 3, 7, and 14 days after I/R. Cytokines were evaluated using magnetic Bio-Plex mouse assays. CD73-/- mutants showed a significantly reduced ejection fraction 14 days after I/R (WT: 57.2±5.6 %; CD73-/-: 39.2±5.8 %; n=12; p<0.01), concomitant with persistent infiltration of immune cells (WT: 2.9±1.2x103; CD73-/-: 9.4±3.7x103 leukocytes/mg heart tissue; n=7-9; p<0.05) as shown by both flow cytometry and 19F MRI. Hearts lacking CD73 contained more myeloid antigen-presenting cells (WT: 1.9±1.0x103; CD73-/-: 5.7±1.3x103/mg heart tissue; p<0.05), but expressed less F4/80, a marker of mature macrophages, associated with reduced tissue levels of IL-10. Moreover, granulocytes, T-helper cells, cytotoxic T-cells, B-cells and inflammatory Ly6chi monocytes were significantly increased in CD73-/- mice. These findings were paralleled by enhanced scar formation in the mutant mice (in adjacent myocardium: WT: 8.7±3.1 % of region of interest (ROI); CD73-/-: 18.1±3.3 % of ROI, p<0.05). Interestingly, the expression of CD73 was found to be significantly increased on all infiltrating T-cell subsets (by 30-65 %) and granulocytes (170%) in the WT demonstrating upregulation of this pathway after I/R. Our findings provide first evidence, that CD73-derived adenosine plays a major role in the healing and remodelling process after I/R by promoting resolution of inflammation and limiting scar development.
- © 2012 by American Heart Association, Inc.