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The neutrophil serine protease PR3 induces shape change of platelets via the Rho/Rho kinase and Ca2+ signaling pathways
Department of Nephrology, Qingyuan City Hospital of Jinan University, Guangdong, China; Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
Department of Experimental and Clinical Medicine, Linköping University, Linköping, Sweden.
Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
Örebro University, School of Medicine, Örebro University, Sweden. Department of Medical and Health Sciences, Linköping University, Linköping, Sweden; .
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2014 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 134, no 2, 418-425 p.Article in journal (Refereed) Published
Abstract [en]

Introduction: Proteinase 3 (PR3) is released from neutrophil azurophilic granules and exerts complex effects on the inflammatory process. PR3 catalyzes the degradation of a number of macromolecules, but the consequences on blood cells are less well defined. In the present study, the effect of PR3 on human platelets was thoroughly investigated.

Methods: The experiments were performed on washed platelets freshly isolated from blood donated by healthy human volunteers. Platelets shape change and aggregation was measured on a Chrono-Log aggregometer. The phosphorylated form of MYPT1 was visualized by immunostaining. Platelet activation was further evaluated by flow cytometry.

Results: PR3 induced platelet shape change but not aggregation. Flow cytometry analysis showed that PR3 induced no P-selectin expression or binding of fibrinogen to the platelets, and it did not change the activation in response to PAR1- or PAR4-activating peptides or to thrombin. Furthermore, Fura-2 measurement and immuno-blotting analysis, respectively, revealed that PR3 stimulated small intracellular Ca2+ mobilization and Thr696-specific phosphorylation of the myosin phosphatase target subunit 1 (MYPT1). Separate treatment of platelets with the Rho/Rho kinase inhibitor Y-27632 and the intracellular Ca2+ chelator BAPTA/AM reduced the shape change induced by PR3 whereas concurrent treatment completely inhibited it.

Conclusion: The data shows that the neutrophil protease PR3 is a direct modulator of human platelets and causes shape change through activation of the Rho/Rho kinase and Ca2+ signaling pathways. This finding highlights an additional mechanism in the complex interplay between neutrophils and platelets.

Place, publisher, year, edition, pages
Oxon, United Kingdom: Elsevier, 2014. Vol. 134, no 2, 418-425 p.
Keyword [en]
ANCA-associated vasculitis, Proteinase PR3, Platelet shape change, Rho/Rho kinase signaling pathway, Ca2+ signaling pathway
National Category
Hematology
Research subject
Medicine
Identifiers
URN: urn:nbn:se:oru:diva-37561DOI: 10.1016/j.thromres.2014.06.001ISI: 000341309200035PubMedID: 24993595Scopus ID: 2-s2.0-84905105637OAI: oai:DiVA.org:oru-37561DiVA: diva2:753147
Note

Funding Agencies:

Swedish Renal Foundation

Asp Foundation

Available from: 2014-10-07 Created: 2014-10-07 Last updated: 2017-10-17Bibliographically approved

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