Transgenic over expression of ectonucleotide triphosphate diphosphohydrolase-1 protects against murine myocardial ischemic injury

Cai, Ming; Huttinger, Zachary M.; He, Heng; Zhang, Weizhi; Li, Feng; Goodman, Lauren; Wheeler, Debra G.; Druhan, Lawrence J.; Zweíer, Jay L.; Dwyer, Karen M.; He, Guanglong; d’Apice, Anthony J.F.; Robson, Simon C.; Cowan, Peter J.; Gumina, Richard J.

doi:10.1016/j.yjmcc.2011.09.003

Cited by 49 publications

(40 citation statements)

References 53 publications

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“…It has been described that ADO induces cardiac Ma to adopt an M2-biased phenotype and drives the timely resolution of postinfarction inflammation (14). Moreover, CD39 and CD73 enzymatic activities exert cardioprotection during myocardial infarction and in ischemic-reperfusion study models (13,36,37). The rate-limiting enzyme in ADO generation is CD73 (22), which is expressed on different cell types.…”

Section: Discussionmentioning

confidence: 99%

CD73 Inhibition Shifts Cardiac Macrophage Polarization toward a Microbicidal Phenotype and Ameliorates the Outcome of Experimental Chagas Cardiomyopathy

Ponce

Sanmarco

Eberhardt

et al. 2016

The Journal of Immunology

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Increasing evidence demonstrates that generation of extracellular adenosine from ATP, which is hydrolyzed by the CD39/CD73 enzyme pair, attenuates the inflammatory response and deactivates macrophage antimicrobial mechanisms. Although CD73 is emerging as a critical pathway and therapeutic target in cardiovascular disorders, the involvement of this ectonucleotidase during myocardial infection has not been explored. Using a murine model of infection with Trypanosoma cruzi, the causal agent of Chagas cardiomyopathy, we observed a sudden switch from the classical M1 macrophage (microbicidal) phenotype toward an alternative M2 (repairing/anti-inflammatory) phenotype that occurred within the myocardium very shortly after BALB/c mice infection. The observed shift in M1/M2 rate correlated with the cardiac cytokine milieu. Considering that parasite persistence within myocardium is a necessary and sufficient condition for the development of the chronic myocarditis, we hypothesized that CD73 activity may counteract cardiac macrophage microbicidal polarization, rendering the local immune response less effective. In fact, a transient treatment with a specific CD73 inhibitor (adenosine 5′-α,β-methylene-diphosphate) enhanced the microbicidal M1 subset predominance, diminished IL-4– and IL-10–producing CD4+ T cells, promoted a proinflammatory cytokine milieu, and reduced parasite load within the myocardium during the acute phase. As a direct consequence of these events, there was a reduction in serum levels of creatine kinase muscle–brain isoenzyme, a myocardial-specific injury marker, and an improvement in the electrocardiographic characteristics during the chronic phase. Our results demonstrate that this purinergic system drives the myocardial immune response postinfection and harbors a promising potential as a therapeutic target.

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Section: Discussionmentioning

confidence: 99%

CD73 Inhibition Shifts Cardiac Macrophage Polarization toward a Microbicidal Phenotype and Ameliorates the Outcome of Experimental Chagas Cardiomyopathy

Ponce

Sanmarco

Eberhardt

et al. 2016

The Journal of Immunology

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“…Ecto-nucleotidase on sympathetic nerve endings attenuates ATP and NA exocytosis in myocardial ischaemia by reducing ATP levels and consequently the prejunctional facilitatory effects of ATP [580]. Conversely, over-expression of E-NTPDase 1/CD39 resulted in enhanced removal of exogenous ATP [618] and protection against murine myocardial ischaemic injury [619]. Since ATP availability greatly increases in myocardial ischaemia, it has been suggested that recombinant E-NTPDase 1/CD39 may offer a novel therapeutic approach to the damage caused by ischaemia by reducing sympathetic activity [618].…”

Section: Ischaemiamentioning

confidence: 99%

Cardiac purinergic signalling in health and disease

Burnstock

Pelleg

2014

Purinergic Signalling

120

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This review is a historical account about purinergic signalling in the heart, for readers to see how ideas and understanding have changed as new experimental results were published. Initially, the focus is on the nervous control of the heart by ATP as a cotransmitter in sympathetic, parasympathetic, and sensory nerves, as well as in intracardiac neurons. Control of the heart by centers in the brain and vagal cardiovascular reflexes involving purines are also discussed. The actions of adenine nucleotides and nucleosides on cardiomyocytes, atrioventricular and sinoatrial nodes, cardiac fibroblasts, and coronary blood vessels are described. Cardiac release and degradation of ATP are also described. Finally, the involvement of purinergic signalling and its therapeutic potential in cardiac pathophysiology is reviewed, including acute and chronic heart failure, ischemia, infarction, arrhythmias, cardiomyopathy, syncope, hypertrophy, coronary artery disease, angina, diabetic cardiomyopathy, as well as heart transplantation and coronary bypass grafts.

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“…Ectonucleotidase on sympathetic nerve endings attenuates ATP and NA exocytosis in myocardial ischemia (by reducing ATP levels and consequently the prejunctional facilitatory effects of ATP) (Sesti et al, 2003). Conversely, overexpression of E-NTPDase 1/CD39 resulted in enhanced removal of exogenous ATP (Corti et al, 2011) and protection against murine myocardial ischemic injury (Cai et al, 2011). Because ATP availability greatly increases in myocardial ischemia, it has been suggested that recombinant E-NTPDase 1/CD39 may offer a novel therapeutic approach to the damage caused by ischemia by reducing sympathetic activity (Corti et al, 2011).…”

Section: Ischemiamentioning

confidence: 99%