PB0405 - Loss of zinc transporters ZIP1 and ZIP3 augments platelet reactivity in response to G protein-coupled receptor agonists and accelerates thrombus formation in vivo

Sunday, July 10, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Co-Author(s)

AE

Amro Elgheznawy

Postdoc
Medical Clinic II, Division of Hepatology, University Hospital Würzburg
Würzburg, Bayern, Germany
Patricia Öftering, MSc

PhD student
University Hospital Würzburg and Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Germany
Würzburg, Bayern, Germany
ME

Maximilian Englert

PhD student
Institute of Experimental Biomedicine I, University Hospital and Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg
Würzburg, Bayern, Germany
FK

Friederike Kaiser

PhD student
Department for Functional Materials in Medicine and Dentistry, University Hospital Würzburg
Würzburg, Bayern, Germany
CK

Charly Kusch

PhD student
Institute of Experimental Biomedicine I, University Hospital Würzburg, Germany and Rudolf Virchow Center for Integrative and Translational Biomaging University of Würzburg, Germany
Würzburg, Bayern, Germany
UG

Uwe Gbureck

Professor
Department for Functional Materials in Medicine and Dentistry, University Hospital Würzburg
Wür, Bayern, Germany
MB

Michael R. Bösl

Professor
Institute of Experimental Biomedicine I, University Hospital and Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, 97080 Würzburg, Germany
Würzburg, Bayern, Germany
BN

Bernhard Nieswandt

Professor
Institute of Experimental Biomedicine - Chair I, University Hospital Würzburg and Rudolf Virchow Center for Integrative and Translational Biomaging, University of Würzburg, Germany
Würzburg, Bayern, Germany

Presenting Author(s)

Timo Vögtle, PhD

Postdoc
University Hospital Würzburg and University of Würzburg
Würzburg, Bayern, Germany

Co-Author(s)

HH

Heike M. Hermanns

Professor
Medical Clinic II, University Hospital Würzburg, University of Würzburg, Germany
Würzburg, Bayern, Germany

Background: Zinc (Zn2+) is an essential micronutrient and also considered as an important mediator for thrombosis and hemostasis. Zn2+ transporters - ZIPs and ZnTs - are widely expressed in eukaryotic cells, including platelets. However, our understanding of the transport mechanisms that regulate Zn2+ homeostasis in platelets is limited.

Aims: To explore the potential role of the well-known Zn2+ transporters ZIP1 and ZIP3 in maintaining platelet Zn2+ homeostasis and in the regulation of platelet function.

Methods: Using mice globally lacking ZIP1 and ZIP3 (ZIP1/3 DKO), we investigated the role of the Zn2+ importers in various in vitro experiments and in vivo experiments of platelet function.

Results: While inductively coupled plasma - mass spectrometry (ICP-MS) measurements indicated unaltered overall Zn2+ concentrations in platelets of ZIP1/3 DKO mice, we observed a significantly delayed and less efficient Zn2+ release upon thrombin-stimulated platelet activation. This resulted in a hyperactive platelet response not only in response to thrombin, but also towards other G protein-coupled receptor (GPCR) agonists. Immunoreceptor tyrosine-based activation (ITAM)-coupled receptor agonist signaling, however, was unaffected. Augmented GPCR responses were accompanied by enhanced Ca2+ signaling and PKC activation. Further functional analysis of ZIP1/3 double deficient mice revealed enhanced platelet aggregation, bigger thrombus volume under flow ex vivo and faster in vivo thrombus formation.

Conclusion(s): The current study identifies ZIP1 and ZIP3 as important regulators for the maintenance of platelet Zn2+ homeostasis and function.

Funding: This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (project number 374031971-TRR 240).