Defective Zn2+ homeostasis in mouse and human platelets with α- and δ-storage pool diseases
Standard
Defective Zn2+ homeostasis in mouse and human platelets with α- and δ-storage pool diseases. / Kiran Gotru, Sanjeev; van Geffen, Johanna P; Nagy, Magdolna; Mammadova-Bach, Elmina; Eilenberger, Julia; Volz, Julia; Manukjan, Georgi; Schulze, Harald; Wagner, Leonard; Eber, Stefan; Schambeck, Christian; Deppermann, Carsten; Brouns, Sanne; Nurden, Paquita; Greinacher, Andreas; Sachs, Ulrich; Nieswandt, Bernhard; Hermanns, Heike M; Heemskerk, Johan W M; Braun, Attila.
in: SCI REP-UK, Jahrgang 9, Nr. 1, 06.06.2019, S. 8333.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Defective Zn2+ homeostasis in mouse and human platelets with α- and δ-storage pool diseases
AU - Kiran Gotru, Sanjeev
AU - van Geffen, Johanna P
AU - Nagy, Magdolna
AU - Mammadova-Bach, Elmina
AU - Eilenberger, Julia
AU - Volz, Julia
AU - Manukjan, Georgi
AU - Schulze, Harald
AU - Wagner, Leonard
AU - Eber, Stefan
AU - Schambeck, Christian
AU - Deppermann, Carsten
AU - Brouns, Sanne
AU - Nurden, Paquita
AU - Greinacher, Andreas
AU - Sachs, Ulrich
AU - Nieswandt, Bernhard
AU - Hermanns, Heike M
AU - Heemskerk, Johan W M
AU - Braun, Attila
PY - 2019/6/6
Y1 - 2019/6/6
N2 - Zinc (Zn2+) can modulate platelet and coagulation activation pathways, including fibrin formation. Here, we studied the (patho)physiological consequences of abnormal platelet Zn2+ storage and release. To visualize Zn2+ storage in human and mouse platelets, the Zn2+ specific fluorescent dye FluoZin3 was used. In resting platelets, the dye transiently accumulated into distinct cytosolic puncta, which were lost upon platelet activation. Platelets isolated from Unc13d-/- mice, characterized by combined defects of α/δ granular release, showed a markedly impaired Zn2+ release upon activation. Platelets from Nbeal2-/- mice mimicking Gray platelet syndrome (GPS), characterized by primarily loss of the α-granule content, had strongly reduced Zn2+ levels, which was also confirmed in primary megakaryocytes. In human platelets isolated from patients with GPS, Hermansky-Pudlak Syndrome (HPS) and Storage Pool Disease (SPD) altered Zn2+ homeostasis was detected. In turbidity and flow based assays, platelet-dependent fibrin formation was impaired in both Nbeal2-/- and Unc13d-/- mice, and the impairment could be partially restored by extracellular Zn2+. Altogether, we conclude that the release of ionic Zn2+ store from secretory granules upon platelet activation contributes to the procoagulant role of Zn2+ in platelet-dependent fibrin formation.
AB - Zinc (Zn2+) can modulate platelet and coagulation activation pathways, including fibrin formation. Here, we studied the (patho)physiological consequences of abnormal platelet Zn2+ storage and release. To visualize Zn2+ storage in human and mouse platelets, the Zn2+ specific fluorescent dye FluoZin3 was used. In resting platelets, the dye transiently accumulated into distinct cytosolic puncta, which were lost upon platelet activation. Platelets isolated from Unc13d-/- mice, characterized by combined defects of α/δ granular release, showed a markedly impaired Zn2+ release upon activation. Platelets from Nbeal2-/- mice mimicking Gray platelet syndrome (GPS), characterized by primarily loss of the α-granule content, had strongly reduced Zn2+ levels, which was also confirmed in primary megakaryocytes. In human platelets isolated from patients with GPS, Hermansky-Pudlak Syndrome (HPS) and Storage Pool Disease (SPD) altered Zn2+ homeostasis was detected. In turbidity and flow based assays, platelet-dependent fibrin formation was impaired in both Nbeal2-/- and Unc13d-/- mice, and the impairment could be partially restored by extracellular Zn2+. Altogether, we conclude that the release of ionic Zn2+ store from secretory granules upon platelet activation contributes to the procoagulant role of Zn2+ in platelet-dependent fibrin formation.
U2 - 10.1038/s41598-019-44751-w
DO - 10.1038/s41598-019-44751-w
M3 - SCORING: Journal article
C2 - 31171812
VL - 9
SP - 8333
JO - SCI REP-UK
JF - SCI REP-UK
SN - 2045-2322
IS - 1
ER -