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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.

SUBMITTER: Sutton NR

PROVIDER: S-EPMC5213916 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Ectonucleotidase CD39-driven control of postinfarction myocardial repair and rupture.

Sutton Nadia R NR Hayasaki Takanori T Hyman Matthew C MC Anyanwu Anuli C AC Liao Hui H Petrovic-Djergovic Danica D Badri Linda L Baek Amy E AE Walker Natalie N Fukase Keigo K Kanthi Yogendra Y Visovatti Scott H SH Horste Ellen L EL Ray Jessica J JJ Goonewardena Sascha N SN Pinsky David J DJ

JCI insight 20170112 1

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+/+ ...[more]

PMID: 28097233

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Project description:ImportanceVentricular septal rupture (VSR) is a rare but life-threatening mechanical complication of acute myocardial infarction associated with high mortality despite prompt treatment. Surgery represents the standard of care; however, only small single-center series or national registries are usually available in literature, whereas international multicenter investigations have been poorly carried out, therefore limiting the evidence on this topic.ObjectivesTo assess the clinical characteristics and early outcomes for patients who received surgery for postinfarction VSR and to identify factors independently associated with mortality.Design, setting, and participantsThe Mechanical Complications of Acute Myocardial Infarction: an International Multicenter Cohort (CAUTION) Study is a retrospective multicenter international cohort study that includes patients who were treated surgically for mechanical complications of acute myocardial infarction. The study was conducted from January 2001 to December 2019 at 26 different centers worldwide among 475 consecutive patients who underwent surgery for postinfarction VSR.ExposuresSurgical treatment of postinfarction VSR, independent of the technique, alone or combined with other procedures (eg, coronary artery bypass grafting).Main outcomes and measuresThe primary outcome was early mortality; secondary outcomes were postoperative complications.ResultsOf the 475 patients included in the study, 290 (61.1%) were men, with a mean (SD) age of 68.5 (10.1) years. Cardiogenic shock was present in 213 patients (44.8%). Emergent or salvage surgery was performed in 212 cases (44.6%). The early mortality rate was 40.4% (192 patients), and it did not improve during the nearly 20 years considered for the study (median [IQR] yearly mortality, 41.7% [32.6%-50.0%]). Low cardiac output syndrome and multiorgan failure were the most common causes of death (low cardiac output syndrome, 70 [36.5%]; multiorgan failure, 53 [27.6%]). Recurrent VSR occurred in 59 participants (12.4%) but was not associated with mortality. Cardiogenic shock (survived: 95 [33.6%]; died, 118 [61.5%]; P < .001) and early surgery (time to surgery ≥7 days, survived: 105 [57.4%]; died, 47 [35.1%]; P < .001) were associated with lower survival. At multivariate analysis, older age (odds ratio [OR], 1.05; 95% CI, 1.02-1.08; P = .001), preoperative cardiac arrest (OR, 2.71; 95% CI, 1.18-6.27; P = .02) and percutaneous revascularization (OR, 1.63; 95% CI, 1.003-2.65; P = .048), and postoperative need for intra-aortic balloon pump (OR, 2.98; 95% CI, 1.46-6.09; P = .003) and extracorporeal membrane oxygenation (OR, 3.19; 95% CI, 1.30-7.38; P = .01) were independently associated with mortality.Conclusions and relevanceIn this study, surgical repair of postinfarction VSR was associated with a high risk of early mortality; this risk has remained unchanged during the last 2 decades. Delayed surgery seemed associated with better survival. Age, preoperative cardiac arrest and percutaneous revascularization, and postoperative need for intra-aortic balloon pump and extracorporeal membrane oxygenation were independently associated with early mortality. Further prospective studies addressing preoperative and perioperative patient management are warranted to hopefully improve the currently suboptimal outcome.

Project description:BackgroundAn important mechanism, by which cancer cells achieve immune escape, is the release of extracellular adenosine into their microenvironment. Adenosine activates adenosine A2A and A2B receptors on immune cells constituting one of the strongest immunosuppressive mediators. In addition, extracellular adenosine promotes angiogenesis, tumor cell proliferation, and metastasis. Cancer cells upregulate ectonucleotidases, most importantly CD39 and CD73, which catalyze the hydrolysis of extracellular ATP to AMP (CD39) and further to adenosine (CD73). Inhibition of CD39 is thus expected to be an effective strategy for the (immuno)therapy of cancer. However, suitable small molecule inhibitors for CD39 are not available. Our aim was to identify drug-like CD39 inhibitors and evaluate them in vitro.MethodsWe pursued a repurposing approach by screening a self-compiled collection of approved, mostly ATP-competitive protein kinase inhibitors, on human CD39. The best hit compound was further characterized and evaluated in various orthogonal assays and enzyme preparations, and on human immune and cancer cells.ResultsThe tyrosine kinase inhibitor ceritinib, a potent anticancer drug used for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer, was found to strongly inhibit CD39 showing selectivity versus other ectonucleotidases. The drug displays a non-competitive, allosteric mechanism of CD39 inhibition exhibiting potency in the low micromolar range, which is independent of substrate (ATP) concentration. We could show that ceritinib inhibits ATP dephosphorylation in peripheral blood mononuclear cells in a dose-dependent manner, resulting in a significant increase in ATP concentrations and preventing adenosine formation from ATP. Importantly, ceritinib (1-10 µM) substantially inhibited ATP hydrolysis in triple negative breast cancer and melanoma cells with high native expression of CD39.ConclusionsCD39 inhibition might contribute to the effects of the powerful anticancer drug ceritinib. Ceritinib is a novel CD39 inhibitor with high metabolic stability and optimized physicochemical properties; according to our knowledge, it is the first brain-permeant CD39 inhibitor. Our discovery will provide the basis (i) to develop more potent and balanced dual CD39/ALK inhibitors, and (ii) to optimize the ceritinib scaffold towards interaction with CD39 to obtain potent and selective drug-like CD39 inhibitors for future in vivo studies.

Dataset Information

Ectonucleotidase CD39-driven control of postinfarction myocardial repair and rupture.

Publications

Ectonucleotidase CD39-driven control of postinfarction myocardial repair and rupture.

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