Cathepsin G-Dependent Modulation of Platelet Thrombus Formation In Vivo by Blood Neutrophils

Neutrophils are consistently associated with arterial thrombotic morbidity in human clinical studies but the causal basis for this association is unclear. We tested the hypothesis that neutrophils modulate platelet activation and thrombus formation in vivo in a cathepsin G-dependent manner. Neutroph...

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Main Authors:	Faraday, Nauder, Schunke, Kathryn, Saleem, Sofiyan, Fu, Juan, Wang, Bing, Zhang, Jian, Morrell, Craig, Dore, Sylvain
Format:	Online
Language:	English
Published:	Public Library of Science 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733958/

id	pubmed-3733958
recordtype	oai_dc
spelling	pubmed-37339582013-08-12 Cathepsin G-Dependent Modulation of Platelet Thrombus Formation In Vivo by Blood Neutrophils Faraday, Nauder Schunke, Kathryn Saleem, Sofiyan Fu, Juan Wang, Bing Zhang, Jian Morrell, Craig Dore, Sylvain Research Article Neutrophils are consistently associated with arterial thrombotic morbidity in human clinical studies but the causal basis for this association is unclear. We tested the hypothesis that neutrophils modulate platelet activation and thrombus formation in vivo in a cathepsin G-dependent manner. Neutrophils enhanced aggregation of human platelets in vitro in dose-dependent fashion and this effect was diminished by pharmacologic inhibition of cathepsin G activity and knockdown of cathepsin G expression. Tail bleeding time in the mouse was prolonged by a cathepsin G inhibitor and in cathepsin G knockout mice, and formation of neutrophil-platelet conjugates in blood that was shed from transected tails was reduced in the absence of cathepsin G. Bleeding time was highly correlated with blood neutrophil count in wildtype but not cathepsin G deficient mice. In the presence of elevated blood neutrophil counts, the anti-thrombotic effect of cathepsin G inhibition was greater than that of aspirin and additive to it when administered in combination. Both pharmacologic inhibition of cathepsin G and its congenital absence prolonged the time for platelet thrombus to form in ferric chloride-injured mouse mesenteric arterioles. In a vaso-occlusive model of ischemic stroke, inhibition of cathepsin G and its congenital absence improved cerebral blood flow, reduced histologic brain injury, and improved neurobehavioral outcome. These experiments demonstrate that neutrophil cathepsin G is a physiologic modulator of platelet thrombus formation in vivo and has potential as a target for novel anti-thrombotic therapies. Public Library of Science 2013-08-05 /pmc/articles/PMC3733958/ /pubmed/23940756 http://dx.doi.org/10.1371/journal.pone.0071447 Text en © 2013 Faraday et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Faraday, Nauder Schunke, Kathryn Saleem, Sofiyan Fu, Juan Wang, Bing Zhang, Jian Morrell, Craig Dore, Sylvain
spellingShingle	Faraday, Nauder Schunke, Kathryn Saleem, Sofiyan Fu, Juan Wang, Bing Zhang, Jian Morrell, Craig Dore, Sylvain Cathepsin G-Dependent Modulation of Platelet Thrombus Formation In Vivo by Blood Neutrophils
author_facet	Faraday, Nauder Schunke, Kathryn Saleem, Sofiyan Fu, Juan Wang, Bing Zhang, Jian Morrell, Craig Dore, Sylvain
author_sort	Faraday, Nauder
title	Cathepsin G-Dependent Modulation of Platelet Thrombus Formation In Vivo by Blood Neutrophils
title_short	Cathepsin G-Dependent Modulation of Platelet Thrombus Formation In Vivo by Blood Neutrophils
title_full	Cathepsin G-Dependent Modulation of Platelet Thrombus Formation In Vivo by Blood Neutrophils
title_fullStr	Cathepsin G-Dependent Modulation of Platelet Thrombus Formation In Vivo by Blood Neutrophils
title_full_unstemmed	Cathepsin G-Dependent Modulation of Platelet Thrombus Formation In Vivo by Blood Neutrophils
title_sort	cathepsin g-dependent modulation of platelet thrombus formation in vivo by blood neutrophils
description	Neutrophils are consistently associated with arterial thrombotic morbidity in human clinical studies but the causal basis for this association is unclear. We tested the hypothesis that neutrophils modulate platelet activation and thrombus formation in vivo in a cathepsin G-dependent manner. Neutrophils enhanced aggregation of human platelets in vitro in dose-dependent fashion and this effect was diminished by pharmacologic inhibition of cathepsin G activity and knockdown of cathepsin G expression. Tail bleeding time in the mouse was prolonged by a cathepsin G inhibitor and in cathepsin G knockout mice, and formation of neutrophil-platelet conjugates in blood that was shed from transected tails was reduced in the absence of cathepsin G. Bleeding time was highly correlated with blood neutrophil count in wildtype but not cathepsin G deficient mice. In the presence of elevated blood neutrophil counts, the anti-thrombotic effect of cathepsin G inhibition was greater than that of aspirin and additive to it when administered in combination. Both pharmacologic inhibition of cathepsin G and its congenital absence prolonged the time for platelet thrombus to form in ferric chloride-injured mouse mesenteric arterioles. In a vaso-occlusive model of ischemic stroke, inhibition of cathepsin G and its congenital absence improved cerebral blood flow, reduced histologic brain injury, and improved neurobehavioral outcome. These experiments demonstrate that neutrophil cathepsin G is a physiologic modulator of platelet thrombus formation in vivo and has potential as a target for novel anti-thrombotic therapies.
publisher	Public Library of Science
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733958/
_version_	1612000666645954560

Cathepsin G-Dependent Modulation of Platelet Thrombus Formation In Vivo by Blood Neutrophils

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