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PMID: 18094327 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Serglycin proteoglycan deletion induces defects in platelet aggregation and thrombus formation in mice.

Blood ·Vol. 111 ·No. 7 ·2008-04-01 ·Pages 3458-67

Woulfe DS, Lilliendahl JK, August S, Rauova L, Kowalska MA, Abrink M, Pejler G, White JG, Schick BP

Abstract

Serglycin (SG), the hematopoietic cell secretory granule proteoglycan, is crucial for storage of specific secretory proteins in mast cells, neutrophils, and cytotoxic T lymphocytes. We addressed the role of SG in platelets using SG-/- mice. Wild-type (WT) but not SG-/- platelets contained chondroitin sulfate proteoglycans. Electron microscopy revealed normal alpha-granule structure in SG-/- platelets. However, SG-/- platelets and megakaryocytes contained unusual scroll-like membranous inclusions, and SG-/- megakaryocytes showed extensive emperipolesis of neutrophils. SG-/- platelets had reduced ability to aggregate in response to low concentrations of collagen or PAR4 thrombin receptor agonist AYPGKF, and reduced fibrinogen binding after AYPGKF, but aggregated normally to ADP. 3H-serotonin and ATP secretion were greatly reduced in SG-/- platelets. The alpha-granule proteins platelet factor 4, beta-thromboglobulin, and platelet-derived growth factor were profoundly reduced in SG-/- platelets. Exposure of P-selectin and alphaIIb after thrombin treatment was similar in WT and SG-/- platelets. SG-/- mice exhibited reduced carotid artery thrombus formation after exposure to FeCl3. This study demonstrates that SG is crucial for platelet function and thrombus formation. We propose that SG-/- platelet function deficiencies are related to inadequate packaging and secretion of selected alpha-granule proteins and reduced secretion of dense granule contents critical for platelet activation.

MeSH Terms
Adenosine Triphosphate/metabolism Animals Blood Platelets/metabolism,ultrastructure Chlorides Ferric Compounds/pharmacology Fibrinogen/genetics,metabolism Hematopoietic Stem Cells/metabolism,pathology Mast Cells/metabolism,pathology Megakaryocytes/metabolism,ultrastructure Mice Mice, Knockout Neutrophils/metabolism,pathology Noxae/pharmacology Oligopeptides/pharmacology P-Selectin/genetics,metabolism Platelet Aggregation/drug effects,genetics Platelet Factor 4/genetics,metabolism Platelet Membrane Glycoprotein IIb/genetics,metabolism Proteoglycans/genetics,metabolism Receptors, Thrombin/genetics,metabolism Secretory Vesicles/genetics,metabolism,ultrastructure Serotonin/metabolism T-Lymphocytes, Cytotoxic/metabolism,pathology Thrombin/genetics,metabolism Thrombosis/genetics,metabolism,pathology Vesicular Transport Proteins/genetics,metabolism beta-Thromboglobulin/genetics,metabolism
Chemicals
Chlorides Ferric Compounds Noxae Oligopeptides P-Selectin Platelet Membrane Glycoprotein IIb Proteoglycans Receptors, Thrombin Vesicular Transport Proteins alanyl-tyrosyl-prolyl-glycyl-lysyl-phenylalanine beta-Thromboglobulin serglycin Serotonin Platelet Factor 4 Adenosine Triphosphate Fibrinogen Thrombin protease-activated receptor 4 ferric chloride
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Woulfe Donna S
Center for Translational Research, Department of Medicine, Thomas Jefferson University, Philadelphia, and Department of Pediatrics, Children's Hospital of Pennsylvania 19107, USA.
Lilliendahl Joanne Klimas
August Shelley
Rauova Lubica
Kowalska M Anna
Abrink Magnus
Pejler Gunnar
White James G
Schick Barbara P
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2007-07-104703
Published
2008-04-01
Epub
2007-00-19
Pages
3458-67
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC2275015
Subset
IM
Grants
NIDDK NIH HHS · K01 DK066218 · United States
NHLBI NIH HHS · R01 HL081241 · United States
NIGMS NIH HHS · R21 GM070630 · United States
NIDDK NIH HHS · K01 DK66218 · United States
External Links
PubMed source DOI: 10.1182/blood-2007-07-104703 PMC Full Text View journal details
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