Ectonucleotidase CD39-driven control of postinfarction myocardial repair and rupture
Nadia R. Sutton, Takanori Hayasaki, Matthew C. Hyman, Anuli C. Anyanwu, Hui Liao, Danica Petrovic-Djergovic, Linda Badri, Amy E. Baek, Natalie Walker, Keigo Fukase, Yogendra Kanthi, Scott H. Visovatti, Ellen L. Horste, Jessica J. Ray, Sascha N. Goonewardena, David J. Pinsky
Nadia R. Sutton, Takanori Hayasaki, Matthew C. Hyman, Anuli C. Anyanwu, Hui Liao, Danica Petrovic-Djergovic, Linda Badri, Amy E. Baek, Natalie Walker, Keigo Fukase, Yogendra Kanthi, Scott H. Visovatti, Ellen L. Horste, Jessica J. Ray, Sascha N. Goonewardena, David J. Pinsky
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Research Article Cardiology Immunology

Ectonucleotidase CD39-driven control of postinfarction myocardial repair and rupture

Abstract

Mechanical complications of myocardial infarction (MI) are often fatal. Little is known about endogenous factors that predispose to myocardial rupture after MI. Ectonucleoside triphosphate diphosphohydrolase (CD39) could be a critical mediator of propensity to myocardial rupture after MI due to its role in modulating inflammation and thrombosis. Using a model of permanent coronary artery ligation, rupture was virtually abrogated in cd39–/– mice versus cd39+/+ controls, with elevated fibrin and collagen deposition and marked neutrophil and macrophage influx. Macrophages were found to display increased surface expression of CD301 and CD206, marking a reparative phenotype, driven by increased extracellular ATP and IL-4 in the infarcted myocardium of cd39–/– mice. A myeloid-specific CD39-knockout mouse also demonstrated protection from rupture, with an attenuated rupture phenotype, suggesting that complete ablation of CD39 provides the greatest degree of protection in this model. Absence of CD39, either globally or in a myeloid lineage–restricted fashion, skews the phenotype toward alternatively activated (reparative) macrophage infiltration following MI. These studies reveal a previously unrecognized and unexpected role of endogenous CD39 to skew macrophage phenotype and promote a propensity to myocardial rupture after MI.

Authors

Nadia R. Sutton, Takanori Hayasaki, Matthew C. Hyman, Anuli C. Anyanwu, Hui Liao, Danica Petrovic-Djergovic, Linda Badri, Amy E. Baek, Natalie Walker, Keigo Fukase, Yogendra Kanthi, Scott H. Visovatti, Ellen L. Horste, Jessica J. Ray, Sascha N. Goonewardena, David J. Pinsky

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Figure 9

Polarization of activated bone marrow–derived macrophages after γATP stimulation.

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Polarization of activated bone marrow–derived macrophages after γATP sti...
Bone marrow–derived macrophages were untreated (NT) or were stimulated with LPS (100 ng/ml), LPS with 100 μm γATP (nonhydrolyzable ATP), or γATP alone for 18 hours. Gene expression of (A) TNF-α, (B) IL-6, and (C) Arg1 was measured using real-time quantitative reverse transcriptase–PCR. LPS drove an inflammatory response as expected, and exposure with γATP as well as LPS reversed this response. n = 3. ANOVA, *P < 0.05, **P < 0.005. Box and whisker plots show median (line within box), upper and lower quartiles (bounds of box), and minimum and maximum values (bars).