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Circulation. 2017 Jun 13;135(24):2389-2402. doi: 10.1161/CIRCULATIONAHA.116.023301. Epub 2017 Apr 4.

Ischemic Cerebroprotection Conferred by Myeloid Lineage-Restricted or Global CD39 Transgene Expression.

Author information

1
From Department of Molecular and Integrative Physiology (A.E.B., D.J.P.) and Department of Internal Medicine (N.R.S., D.P.-D, H.L., J.R., Y.K., D.J.P.), Division of Cardiovascular Medicine University of Michigan Medical Center, Ann Arbor; and Section of Cardiology, VA Ann Arbor Healthcare System, MI (J.P.).
2
From Department of Molecular and Integrative Physiology (A.E.B., D.J.P.) and Department of Internal Medicine (N.R.S., D.P.-D, H.L., J.R., Y.K., D.J.P.), Division of Cardiovascular Medicine University of Michigan Medical Center, Ann Arbor; and Section of Cardiology, VA Ann Arbor Healthcare System, MI (J.P.). dpinsky@med.umich.edu.

Abstract

BACKGROUND:

Cerebral tissue damage after an ischemic event can be exacerbated by inflammation and thrombosis. Elevated extracellular ATP and ADP levels are associated with cellular injury, inflammation, and thrombosis. Ectonucleoside triphosphate diphosphohydrolase-1 (CD39), an enzyme expressed on the plasmalemma of leukocytes and endothelial cells, suppresses platelet activation and leukocyte infiltration by phosphohydrolyzing ATP/ADP. To investigate the effects of increased CD39 in an in vivo cerebral ischemia model, we developed a transgenic mouse expressing human CD39 (hCD39).

METHODS:

A floxed-stop sequence was inserted between the promoter and the hCD39 transcriptional start site, generating a mouse in which the expression of hCD39 can be controlled tissue-specifically using Cre recombinase mice. We generated mice that express hCD39 globally or in myeloid-lineage cells only. Cerebral ischemia was induced by middle cerebral artery occlusion. Infarct volumes were quantified by MRI after 48 hours.

RESULTS:

Both global and transgenic hCD39- and myeloid lineage CD39-overexpressing mice (transgenic, n=9; myeloid lineage, n=6) demonstrated significantly smaller cerebral infarct volumes compared with wild-type mice. Leukocytes from ischemic and contralateral hemispheres were analyzed by flow cytometry. Although contralateral hemispheres had equal numbers of macrophages and neutrophils, ischemic hemispheres from transgenic mice had less infiltration (n=4). Transgenic mice showed less neurological deficit compared with wild-type mice (n=6).

CONCLUSIONS:

This is the first report of transgenic overexpression of CD39 in mice imparting a protective phenotype after stroke, with reduced leukocyte infiltration, smaller infarct volumes, and decreased neurological deficit. CD39 overexpression, either globally or in myeloid lineage cells, quenches postischemic leukosequestration and reduces stroke-induced neurological injury.

KEYWORDS:

CD39; inflammation

PMID:
28377485
PMCID:
PMC5643044
DOI:
10.1161/CIRCULATIONAHA.116.023301
[Indexed for MEDLINE]
Free PMC Article

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