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 7

Creation of myeloid CD39 conditional knockout.

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Creation of myeloid CD39 conditional knockout. (A) LoxP- and Frt-flanked...
(A) LoxP- and Frt-flanked neomycin sites were introduced to flank exon 1 of the native cd39 locus using homologous recombination. Neomycin was subsequently removed from all progeny using Flp recombinase. (B) Southern blot demonstrating successful transfer of the cd39flox allele in the F1 generation of progeny, the stem cell line identified with successful homologous recombination at the CD39 locus, and control C57BL/6 DNA. (C) CD39 expression by genotype. Flow cytometry demonstrating CD39 expression on myeloid cells (peritoneal macrophages) in cd39+/+, cd39–/–, cd39flox/flox, and cd39flox/floxLysMCre/– mice. Global CD39 knockouts were confirmed as having no CD39 expression, and myeloid-specific CD39 knockouts were confirmed as having no myeloid CD39 expression. n = 4 per group. 1-way ANOVA, ***P < 0.0001. Box and whisker plots show median (line within box), upper and lower quartiles (bounds of box), and minimum and maximum values (bars).