RATIONALE: Ecto-5'-nucleotidase (CD73) on immune cells is emerging as a critical pathway and therapeutic target in cardiovascular and autoimmune disorders. 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) cardiac adenosine release was augmented 7 days after ischemia/reperfusion in control mice but reduced by 90% in CD73 mutants, (3) impaired healing involves M1-driven immune response with increased tumor necrosis factor-α and interleukin-17, as well as decreased transforming growth factor-β and interleukin-10, and (4) CD73(-/-) mice displayed infarct expansion accompanied by an immature replacement scar and diffuse ventricular fibrosis. Studies on mice after bone marrow transplantation revealed that CD73 present on immune cells is a major determinant promoting cardiac healing. CONCLUSIONS: These results, together with the upregulation of CD73 on immune cells after ischemia/reperfusion, demonstrate the crucial role of purinergic signaling during cardiac healing and provide groundwork for novel anti-inflammatory strategies in treating adverse cardiac remodeling.
RATIONALE: Ecto-5'-nucleotidase (CD73) on immune cells is emerging as a critical pathway and therapeutic target in cardiovascular and autoimmune disorders. 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) cardiac adenosine release was augmented 7 days after ischemia/reperfusion in control mice but reduced by 90% in CD73 mutants, (3) impaired healing involves M1-driven immune response with increased tumor necrosis factor-α and interleukin-17, as well as decreased transforming growth factor-β and interleukin-10, and (4) CD73(-/-) mice displayed infarct expansion accompanied by an immature replacement scar and diffuse ventricular fibrosis. Studies on mice after bone marrow transplantation revealed that CD73 present on immune cells is a major determinant promoting cardiac healing. CONCLUSIONS: These results, together with the upregulation of CD73 on immune cells after ischemia/reperfusion, demonstrate the crucial role of purinergic signaling during cardiac healing and provide groundwork for novel anti-inflammatory strategies in treating adverse cardiac remodeling.
Authors: Thorsten Gnad; Saskia Scheibler; Ivar von Kügelgen; Camilla Scheele; Ana Kilić; Anja Glöde; Linda S Hoffmann; Laia Reverte-Salisa; Philipp Horn; Samet Mutlu; Ali El-Tayeb; Mathias Kranz; Winnie Deuther-Conrad; Peter Brust; Martin E Lidell; Matthias J Betz; Sven Enerbäck; Jürgen Schrader; Gennady G Yegutkin; Christa E Müller; Alexander Pfeifer Journal: Nature Date: 2014-10-15 Impact factor: 49.962
Authors: Roman Covarrubias; Elena Chepurko; Adam Reynolds; Zachary M Huttinger; Ryan Huttinger; Katherine Stanfill; Debra G Wheeler; Tatiana Novitskaya; Simon C Robson; Karen M Dwyer; Peter J Cowan; Richard J Gumina Journal: Arterioscler Thromb Vasc Biol Date: 2016-07-14 Impact factor: 8.311
Authors: Daniela Friebe; Tao Yang; Timo Schmidt; Nadine Borg; Bodo Steckel; Zhaoping Ding; Jürgen Schrader Journal: PLoS One Date: 2014-04-18 Impact factor: 3.240