Serglycin proteoglycan deletion induces defects in platelet aggregation and thrombus formation in mice.
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.
Woulfe
Donna S
DS
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
JK
August
Shelley
S
Rauova
Lubica
L
Kowalska
M Anna
MA
Abrink
Magnus
M
Pejler
Gunnar
G
White
James G
JG
Schick
Barbara P
BP
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism* / Q000648:ultrastructure; D002712:Chlorides; D005290:Ferric Compounds / Q000494:pharmacology; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology; D008533:Megakaryocytes / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D009676:Noxae / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics; D010978:Platelet Factor 4 / Q000235:genetics / Q000378:metabolism; D040201:Platelet Membrane Glycoprotein IIb / Q000235:genetics / Q000378:metabolism; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000235:genetics / Q000378:metabolism; D022142:Secretory Vesicles / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D012701:Serotonin / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism / Q000473:pathology; D013917:Thrombin / Q000235:genetics / Q000378:metabolism; D013927:Thrombosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D001620:beta-Thromboglobulin / Q000235:genetics / Q000378:metabolism
D002712:Chlorides; D005290:Ferric Compounds; D009676:Noxae; D009842:Oligopeptides; D019007:P-Selectin; D040201:Platelet Membrane Glycoprotein IIb; D011509:Proteoglycans; D018179:Receptors, Thrombin; D033921:Vesicular Transport Proteins; C455901:alanyl-tyrosyl-prolyl-glycyl-lysyl-phenylalanine; D001620:beta-Thromboglobulin; C075430:serglycin; D012701:Serotonin; D010978:Platelet Factor 4; D000255:Adenosine Triphosphate; D005340:Fibrinogen; D013917:Thrombin; C112908:protease-activated receptor 4; C024555:ferric chloride